Multi-cyclic compound and method of use

ABSTRACT

The present invention relates to chemical compounds having a general formula I  
                 
 
wherein A, B, C 1 , C 2 , D, L 1 , L 2  and R 3-4  are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Tie-2 and Aurora kinase enzymes thereby influencing angiogenesis and the process of cell cycle and cell proliferation, respectively, to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of various protein kinases.

This application claims the benefit of U.S. Provisional Application No.60/776,507, filed Feb. 24, 2006, which is hereby incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical agents and, morespecifically, to multi-cyclic compounds, compositions, uses and methodsfor treating oncological disorders, including cancer.

BACKGROUND OF THE INVENTION

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating cellproliferation, activation, and/or differentiation and cell-cyclingprocesses. Uncontrolled or excessive kinase activity has been observedin many disease states including benign and malignant proliferativedisorders as well as diseases resulting from inappropriate activation ofvarious cellular processes. In addition, endothelial cell specificreceptor protein tyrosine kinases, such as Tie-2, mediate the angiogenicprocess and are, therefore, involved in supporting the progression ofcancers and other diseases involving uncontrolled vascularization.

The ability to regulate vascular growth has potential utility fortreatment of ischemia-induced pathologies such as myocardial infarction,coronary artery disease, peripheral vascular disease, and stroke. Thesprouting of new vessels and/or the expansion of small vessels inischemic tissues prevents ischemic tissue death and induces tissuerepair. Regulating angiogenesis by inhibiting certain recognizedpathways in this process would therefore, be useful in treatingdiseases, such as ocular neovascularization, including retinopathies(including diabetic retinopathy), age-related macular degeneration,

psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatorydisease rheumatoid arthritis, chronic inflammatory disorders such aschronic asthma, arterial or post-transplantational atherosclerosis,endometriosis, and neoplastic diseases such as leukemias, otherwiseknown to be associated with deregulated angiogenesis.

One target identified in the cascade of events leading to angiogenesisis the Tie receptor family. The Tie-1 and Tie-2 receptors aresingle-transmembrane, tyrosine kinase receptors (Tie stands for tyrosinekinase receptors with immunoglobulin and EGF homology domains). Tie-2 isan endothelial cell specific receptor tyrosine kinase, which is involvedin angiogenic processes, such as vessel branching, sprouting,remodeling, maturation and stability. Biological models suggest that thestimulation of Tie-2 by the Ang1 ligand is directly involved in thebranching, sprouting and outgrowth of new vessels, and recruitment andinteraction of periendothelial support cells important in maintainingvessel integrity and inducing quiescence. The absence of Ang1stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation byAng2, which is produced at high levels at sites of vascular regression,may cause a loss in vascular structure and matrix contacts resulting inendothelial death, especially in the absence of growth/survival stimuli.

Recently, upregulation of Tie-2 expression has been found in thevascular synovial pannus of arthritic joints of humans, consistent withthe role in inappropriate neovasculariation. This finding suggests thatTie-2 plays a role in the progression of rheumatoid arthritis. Pointmutations producing constitutively activated forms of Tie-2 have beenidentified in association with human venous malformation disorders.Tie-2 inhibitors would, therefore, be useful in treating such disorders,as well as in other instances of improper neovasacularization. However,with the recent recognition of Ang3 and Ang4 as additional Tie-2 bindingligands, targeting a Tie-2 ligand-receptor interaction as ananti-angiogenic therapeutic approach is less favorable. Accordingly, aTie-2 receptor kinase inhibition approach has become a strategy ofchoice.

Cancer and related oncological conditions are also caused by unregulatedcell proliferation. Damage to one or more genes, responsible for thecellular pathways, which control progress of proliferation through thecell cycle, typically causes the loss of normal regulation of cellproliferation. These genes code for various proteins, which participatein a cascade of events, including protein phosphorylation, leading tocell-cycling progression and cell proliferation. Various kinase proteinshave been identified, which play roles in the cell cycling cascade andin protein phosphorylation in particular.

One class of proteins found to play a part in cell cycling and,therefore, cell proliferation is the Aurora kinase family of proteins.Aurora kinases are enzymes of the serine/threonine kinase family ofproteins, which play an important role in protein phosphorylation duringthe mitotic phase of the cell cycle. There are three known members ofthe Aurora kinase family, Aurora A, Aurora B and Aurora C, also commonlyreferred to as Aurora 2, Aurora 1, and Aurora 3, respectively.

Aurora kinases appear to be viable targets for the treatment of cancer.Aurora kinases are overexpressed in various types of cancers, includingcolon, breast, lung, pancrease, prostate, bladder, head, neck, cervix,and ovarion cancers. The Aurora-A gene is part of an amplicon found in asubset of breast, colon, ovarian, liver, gastric and pancreatic tumors.Aurora-B has also been found to be overexpressed in most major tumortypes. Overexpression of Aurora-B in rodent fibroblasts inducestransformation, suggesting that Aurora-B is oncogenic. More recently,Aurora-B mRNA expression has been linked to chromosomal instability inhuman breast cancer. (Y. Miyoshi et al., Int. J. Cancer, 92:370-373(2001)).

Further, inhibition of one or more of the Aurora kinases by severalparties has been shown to inhibit cell proliferation and triggerapoptosis in several tumor cell lines. Particularly, inhibition ofAurora has been found to arrest cell cycling and promote programmed celldeath via apoptosis. Accordingly, there has been a strong interest infinding inhibitors of Aurora kinase proteins.

Many classes of compounds have been proposed to generally orspecifically inhibit kinase activity, including Aurora kinase. Forexample, WO 03/000660 describes substituted phenyl compounds, U.S. Pat.No. 6,143,764 describes substituted quinolines, WO 02/32872 describessubstituted quinolines, WO 00/47212 describes substituted quinazolinederivatives, WO 04/039774 describes aza-quinazolinones for treatingcancer via inhibiton of Aurora kinase, WO 04/037814 describesindazolinones for treating cancer via inhibiton of Aurora-2 kinase, WO04/016612 describes 2, 6, 9-substituted purine derivatives for treatingcancer via inhibiton of Aurora kinase, WO 04/000833 describes tri- andtetra-substituted pyrimidine compounds useful for treatingAurora-mediated diseases and U.S. Pat. No. 6,919,338 and WO 03/055491each describe substituted quinazoline derivatives as inhibitors ofAurora-2 kinase.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful intreating oncological conditions and/or disease states related to kinaseactivity and, in particular, in treating active angiogenesis,cell-cycling disorders and related diseases, including cancer. In oneembodiment of the invention, the compounds, including pharmaceuticallyacceptable salts thereof, are generally defined by Formula I

wherein A, B, C¹, C², D, L¹, L² and R³⁻⁴ are defined herein.

In another embodiment, the invention further provides compounds ofFormulas II and III, which are similar in structure to Formula I above.

The invention also provides processes for making compounds of FormulasI-III, as well as intermediates useful in such processes. In oneembodiment, there is a method of making a compound of Formulas I-III,the method comprising the step of reacting compound of Formula A

with a compound of Formula B

wherein A, B, C¹, C², D, L¹, L² and R³⁻⁴ are defined herein and X is ahalogen.

The compounds provided by the invention have kinase modulatory activityand, in particular, inhibitory activity, with respect to Tie-2 and/orAurora kinase kinase. To this end, the invention further provides theuse of these compounds, as well as their pharmaceutically acceptablesalts, in the preparation and/or manufacture of a medicament orpharmaceutical composition for therapeutic, prophylactic, acute orchronic treatment of an angiogenesis mediated disease state or acell-cycling mediated disorder, including those described herein. Thus,the compounds described herein are useful as anti-cancer agents. Moreparticularly, these compounds are useful in the manufacture ofmedicaments to attenuate or prevent disorders through inhibition ofTie-2 and/or Aurora kinase activity. For example, in one embodiment, theinvention provides a pharmaceutical composition comprising atherapeutically-effective amount of a compound of Formula I, II or IIIin association with a least one pharmaceutically-acceptable carrier,adjuvant or diluent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, compounds, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts, derivatives andprodrugs thereof, useful for treating Tie-2 and/or Aurorakinase-mediated conditions, are defined by Formula I:

Wherein A is

-   -   wherein each of A¹ and A³ independently, is N or CR⁸ and A² is        NR⁹, O or S;

B is a fully unsaturated 5-6 membered first monocyclic ring, said firstring (1) formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, (2) optionally fused to a partially or fullysaturated or fully unsaturated 5-6 membered second monocyclic ringformed of carbon atoms optionally including 1-3 heteroatoms selectedfrom O, N, or S, and (3) wherein 0, 1, 2 or 3 atoms of each of saidfirst and second ring is optionally substituted independently with 1-4substituents of R⁵;

C¹ is N or CR¹⁰;

C² is N or CH;

D is

-   -   wherein D¹ is N or CR¹¹;    -   D² is N or CR¹²;    -   R¹ is H, OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,        (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵, wherein n is 0, 1, 2, 3        or 4;    -   R^(1a) is H, CN or C₁₋₁₀alkyl;    -   alternatively R¹ taken together with either of R¹¹ and R^(1a)        and the carbon or nitrogen atoms to which they are attached form        a partially or fully unsaturated 5- or 6-membered ring of carbon        atoms optionally including 1-3 heteroatoms selected from O, N        and S, and the ring optionally substituted independently with        1-4 substituents of R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵,        COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵; and    -   R² is SR¹⁴, OR¹⁴, SR^(15 , OR) ¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,        C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,        C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,        NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵,        S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,        NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵        or R¹⁵;

L¹ is NR³, O, S, C(O), S(O), SO₂ or CR³R³;

L² is NR³, O, S, C(O), S(O), SO₂ or CR³R³;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-4 substituents of R¹³, R¹⁴or R¹⁵;

each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;

alternatively, R⁶ and R⁷ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N, or S, and the ring optionally substituted independently with 1-4substituents of R¹³, R¹⁴ or R¹⁵;

R⁹ is R¹⁵;

each of R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵,C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴,S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-3 substituents of R¹⁵; and

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,dietbylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

provided that (1) no more than one of D¹ and D² is N, and (2) each of L¹and L² is, independently, bound to the first ring of B.

Accordingly, the above embodiment does not encompass triazine compounds,wherein both D¹ and D² are N, respectively. Triazine compounds (FormulaIII) of the present invention are described in another embodimenthereinbelow. In addition, the above embodiment includes only thosecompounds wherein both linkers L¹ and L² are bound to the first ring ofB, and not compounds wherein one linker is attached to one ring of afused bicyclic B ring while the second linker is attached to the secondring of B.

In another embodiment, the invention includes compounds wherein C¹ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein C² is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein C¹ isCR¹⁰, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein C² is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D is

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D is

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R^(1a)is H, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R^(1a) ais CN or C₁₋₁₀alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein D¹ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D² is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D¹ isCR¹¹, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D² isCR¹², in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein D² is Nand D¹ is CR¹¹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein D¹ is Nand D² is CR¹², in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein C¹ isCR¹⁰, C² is N and R² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isNR³, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isNR¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isNH, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ is O,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ is S,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isS(O), in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isSO₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isCR³R³, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isCHR¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isCH₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isNR³, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isNR¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isNH, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² is O,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² is S,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isS(O), in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isSO₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isCR³R³, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isCHR¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L² isCH₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ isNR¹⁴R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ isNR¹⁵R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ isOR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, or (CHR¹⁵)_(n)R¹⁴ or (CHR¹⁵)_(n)R¹⁵ wherein n is0, 1, 2, 3 or 4, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R¹ isR¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein each ofR², R³, R⁴and R⁵, independently, is H, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein each ofR², R³, R⁴ and R⁵, independently, is NR¹⁴R¹⁵, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein each ofR², R³, R⁴and R⁵, independently, is NR¹⁵R¹⁵, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein each ofR², R³, R⁴ and R⁵, independently, is R¹⁵, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein R² is H,halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein each ofR³, R⁴ and R⁵, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ orNR¹⁵C(O)C(O)NR¹⁵R¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein eitherof R³ or R⁴, independently, taken together with R¹⁰ and the carbon atomsto which they are attached form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L¹ isNR¹⁵, O, CHR¹⁵, S, C(O), S(O) or SO₂ and R² is H, halo, NO₂, CN,C₁₋₁₀alkyl or C₁₋₁₀alkoxyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein each ofL¹ and L², independently, is CHR¹⁵, NR¹⁵, O, S, or C(O); R² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl; each of R³, R⁴ and R⁹,independently is H; and C¹ is CR¹⁰, in conjunction with any of the aboveor below embodiments.

In another embodiment, the invention includes compounds wherein thefirst monocyclic ring of B is phenyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl,oxadiazolyl, isoxazolyl, or isothiazolyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein thefirst monocyclic ring of B is a fully unsaturated 6-membered ring, andL¹ and L², together, are para to one another on said first monocyclicring of B, in conjunction with any of the above or below embodiments.

In the immediately preceeding embodiment, the invention includescompounds wherein R⁶ and R⁷ taken together with the carbon atoms towhich they are attached form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 nitrogen atoms,and the ring optionally substituted independently with 1-4 substituentsof R¹³, R¹⁴ or R¹⁵, in conjunction with any of the above or belowembodiments.

In the immediately preceeding embodiment, the invention includescompounds wherein R⁶ and R⁷ taken together with the carbon atoms towhich they are attached form a phenyl ring optionally including 1-3nitrogen atoms, and the ring optionally substituted independently with1-4 substituents of R¹³, R¹⁴ or R¹⁵, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein A is

wherein A¹ is N and A² is NH, O or S, in conjunction with any of theabove or below embodiments.

In the immediately preceeding embodiment, the invention includescompounds wherein R⁶ and R⁷ taken together with the carbon atoms towhich they are attached form a phenyl ring optionally substitutedindependently with 1-4 substituents of R¹⁵, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein A is

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A is

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A is

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A is

in conjunction with any of the above or below embodiments.

In the previous three embodiments, the invention includes compoundswherein A¹ is N, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A¹ is CR⁸, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A³ is N, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A³ is CR⁸, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A² is NR⁹, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A² is NH, in conjunction with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A² is N—C₁₋₁₀-alkyl, in conjunction with any of the above orbelow embodiments.

In the previous three embodiments, the invention includes compoundswherein A² is O, in conjunction. with any of the above or belowembodiments.

In the previous three embodiments, the invention includes compoundswherein A² is S, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include C₁₋₁₀alkyl,C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl, heteroaryl,heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R¹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R¹ takentogether with R¹¹ to form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N and S, and the ring optionally substitutedindependently with 1-4 substituents of R¹⁵, halo, haloalkyl, oxo, NO₂,CN, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵R¹⁵ orNR¹⁴R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, oxo, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, NR¹⁴R¹⁵ C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁵R¹⁵,C(O)NR¹⁴R¹⁵, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵C(O)C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or C₁₋₁₀alkyl,C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl or C₄₋₈cycloalkenyl, whereinthe C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl andC₄₋₈cycloalkenyl is optionally substituted with one or more substituentsof R¹⁵, as R², in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C₁₋₁₀alkyl, C₁₋₁₀alkenyl orC₁₋₁₀alkynyl, wherein the C₁₋₁₀loalkyl, C₁₋₁₀alkenyl and C₁₋₁₀alkynyl,is optionally substituted with one or more substituents of R¹⁵, as R²,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C₁₋₁₀alkyl,C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl, heteroaryl,heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R², inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R¹ takentogether with R^(1a) to form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N and S, and the ring optionally substitutedindependently with 1-4 substituents of R¹⁵, halo, haloalkyl, oxo, NO₂,CN, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵R¹⁵ orNR¹⁴R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C₁₋₁₀alkyl,C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl, heteroaryl,heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R³, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C₁₋₁₀alkyl,C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl, heteroaryl,heterocyclyl; heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R⁴, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, oxo, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, NR¹⁴R¹⁵, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁵R¹⁵, C(O)NR¹⁴R¹⁵, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵C(O)C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or C₁₋₁₀alkyl,C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl or C₄₋₈cycloalkenyl, whereinthe C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl andC₄₋₈cycloalkenyl is optionally substituted with one or more substituentsof R¹⁵, as R⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, Cl, Br, F,I, CF₃, CF₂CF₃, NO₂, CN, acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkylamino-, benzyl or phenyl as R⁵, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, oxo, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, NR¹⁴R¹⁵, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁵R¹⁵, C(O)NR¹⁴R¹⁵, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵C(O)C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or C₁₋₁₀alkyl,C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl or C₄₋₈cycloalkenyl, whereinthe C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₃₋₈cycloalkyl andC₄₋₈cycloalkenyl is optionally substituted with one or more substituentsof R¹⁵, as R⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, Cl, Br, F,I, CF₃, CF₂CF₃, NO₂, CN, acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkylamino-, benzyl or phenyl as R⁶, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, haloalkoxyl, CN, OH, NO₂, NH₂, SH, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl orC₁₋₁₀-thioalkoxyl as R⁷, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, C₁₋₁₀-alkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino- orC₁₋₁₀-alkoxyl as R⁷, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, haloalkoxyl, CN, OH, NO₂, NH₂, SH, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₄₋₁₀-alkylamino-, C₁₋₁₀-alkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxylas R⁸, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, C₁₋₁₀-alkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino- orC₁₋₁₀-alkoxyl as R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵ or C(O)R¹⁵ as R⁹, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R¹⁰, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, NR¹⁴R¹⁵, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, C(S)R¹⁵, C(S)NR¹⁵R¹⁵, NR¹⁵C(S)R¹⁵,NR¹⁵C(S)NR¹⁵R¹⁵, S(O)₂R¹³, S(O)₂NR¹³R¹³, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹³or NR¹⁵S(O)₂R¹⁵ as R¹⁰, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, halo,haloalkyl, NO₂, CN, SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, NR¹⁴R¹⁵, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, C(S)R¹⁵, C(S)NR¹⁵R¹⁵, NR¹⁵C(S)R¹⁵,NR¹⁵C(S)NR¹⁵R¹⁵, S(O)₂R¹³, S(O)₂NR¹³R¹³, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹³or NR¹⁵S(O)₂R¹⁵ as R¹², in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include cyclopropyl,cyclobutyl, cyclopentyl, cyclobexyl, tetrahydrofuranyl,tetrahydropyrrolyl, pyranyl, phenyl, naphthyl, furanyl, pyrrolyl,thiophenyl, indolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl,benzothiophenyl, indolinyl, phthalazinyl, benzimidazolyl,benzopyrazolyl, benzoxazolyl, benzothiozolyl, benzisoxazolyl,piperidinyl, piperazinyl, morpholinyl, each of which is optionallyindependently substituted with 1-3 substituents of R¹⁵, as R¹⁴, inconjunction with any of the above or below embodiments.

In yet another embodiment of the invention, compounds useful fortreating angiogenesis and cancer are generally defined by Formula II:

wherein A¹ is N or CR⁸;

A² is NR⁹, O or S;

A′ is phenyl, pyridine, pyrimidine or pyridazine, each of which isoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵;

each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided that nomore than two of B¹, B², B³ and B⁴ is N;

alternatively, each of B¹ and B², independently, is CR⁵, wherein both R⁵groups taken together with the carbon atoms to which they are attachedform a 5- or 6-membered ring of carbon atoms, said ring optionallyincluding 1-4 heteroatoms selected from N, O or S, and optionallysubstituted with 1-3 substituents of R¹³, R¹⁴ or R¹⁵;

C¹ is N or CR¹⁰;

D¹ is N or CR¹¹;

D² is N or CR¹²;

L¹ is NR³, O, S or CR³R³;

L² is NR³, O, S or CR³R³;

R^(1 is OR) ¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,(CHR¹⁵)_(n)R¹⁴(CHR¹⁵)_(n)R¹⁵ or R¹⁵, wherein n is 0, 1, 2, 3 or 4;

alternatively R¹ and R¹¹ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N and S, and the ring optionally substituted independently with 1-4substituents of R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵;

R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵ S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-4 substituents of R¹³, R¹⁴or R¹⁵;

each R¹⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

R⁸ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

R⁹ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₁₋₁₀-alkoxyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alky, C₁₋₁₀-alkoxyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, and ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

each of R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-3 substituents of R¹⁵; and

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

provided that no more than one of D¹ and D² is N.

In another embodiment, the invention includes compounds of Formula II,wherein:

A¹ is N;

A² is NR⁹, O or S;

each of B¹, B², B³ and B⁴, independently, is CR⁵;

C¹ is CR¹⁰;

D¹ is N or CR¹¹;

D² is N or CR¹²;

L¹ is NH, O or S;

L² is NH, O or S;

R¹ is H, halo, haloalkyl, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, NHR¹⁴, NHR¹⁵, OR¹⁵, SR¹⁵ or CH₂R¹⁵;

R² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl;

each of R³ and R⁴, independently, is SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

each R⁵ is, independently, is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁵), S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or R¹⁵; and

R⁸ is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵ or R¹⁵;

R⁹ is H, CN, acetyl or C₁₋₁₀-alkyl; and

each of R¹⁰, R¹¹ and R¹², independently, is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵ or R¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds of Formula II,wherein:

R¹ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵;alternatively R¹ and R¹¹ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N and S, and the ring optionally substituted independently with 1-4substituents of R¹⁵;

R² is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl;

each of R³ and R⁴, independently, is H, halo, haloalkyl, CN, NO₂, NH₂,OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylanine,diisopropylamine, benzyl or phenyl;

each R⁵ is, independently, is H, halo, haloalkyl, CN, NO₂, NH₂, OH,methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine;

R⁸ is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine or diisopropylamine;

R⁹ is H or C₁₋₁₀-alkyl; and

each of R¹⁰, R¹¹ and R¹², independently, is H, halo, haloalkyl, CN, NO₂,NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine, in conjunction with any of the above or belowembodiments.

The embodiments for various of the elements described herein above withrespect to compounds of Formula I also apply to compounds of Formula II,where appropriate, as will be appreciated by those skilled in the art.

In another embodiment, the invention includes compounds of Formula III

wherein A¹ is N or CR⁸;

A² is NR⁹, O or S;

each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided that nomore than two of B¹, B², B³ and B⁴ is N;

C¹ is N or CR¹⁰;

L¹ is O, S, C(O), S(O), SO₂ or CR³R³;

L² is NR³, O, S or CR³R³;

R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴,(CHR¹⁵)_(n)R¹⁵ or R¹⁵;

R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵;

each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;

alternatively, R⁶ and R⁷ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N, or S, and the ring optionally substituted independently with 1-4substituents of R¹³, R¹⁴ or R¹⁵;

R⁹ is R¹⁵;

each of R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-3 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C-₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4.

The embodiments for various of the elements described herein above withrespect to compounds of Formula I also apply to compounds of FormulaIII, where appropriate, as will be appreciated by those skilled in theart.

In yet another embodiment, Formulas I, II and III include the exemplarycompounds and derivatives, progrugs, solvates, tautomers andpharmaceutically acceptable salt forms thereof, intermediates relatedthereto, which are described in the Examples herein.

DEFINITIONS

The following definitions should further assist in understanding theinvention and its scope as described herein.

The terms “agonist” and “agonistic” when used herein refer to ordescribe a molecule which is capable of, directly or indirectly,substantially inducing, promoting or enhancing biological activity of abiological molecule, such as an enzyme or receptor, including Tie-2 andAurora kinase.

“Angiogenesis” is defined as any alteration of an existing vascular bedor the formation of new vasculature which benefits tissue perfusion.This includes the formation of new vessels by sprouting of endothelialcells from existing blood vessels or the remodeling of existing vesselsto alter size, maturity, direction and/or flow properties to improveblood perfusion of tissue.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include, withoutlimitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by unregulated levels of Tie-2 and/or Aurora kinase inthe mammal.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The term “mammal” as used herein refers to any mammal classified as amammal, including humans, cows, horses, dogs and cats. In one embodimentof the invention, the mammal is a human.

A “pharmaceutically-acceptable derivative” denotes any salt (alsoreferred to as “pharmaceutically-acceptable salt”), ester of a compoundof this invention, or any other compound which upon administration to apatient is capable of providing (directly or indirectly) a compound ofthis invention, or a metabolite or residue thereof, characterized by theability to treat a condition related to the activity of one or morekinase enzymes.

The phrase “therapeutically-effective” is intended to quantify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies. For example, effective neoplastictherapeutic agents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

The terms “ring” and “ring system” refer to a one or more rings,typically fused together where more than one ring, comprising thedelineated number of atoms, said atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, aswell as any substitutents thereon, may be attached at any atom thatallows a stable compound to be formed. The term “non-aromatic” ring orring system refers to the fact that at least one, but not necessarilyall, rings in a bicyclic or tricyclic ring system is not fullyunsaturated.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalspreferably having alpha to beta number of carbon atoms. For example aC₁-C₁₀ alkyl is an alkyl comprising 1 to 10 carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Itis contemplated herein that alkyl radicals may be optionally substitutedwith various substituents, where indicated. The term “alkylenyl”embraces bridging divalent alkyl radicals such as methylenyl andethylenyl.

The term “alkenyl”, alone or in combination, embraces linear or branchedradicals having at least one carbon-carbon double bond of two or morecarbon atoms. Examples of alkenyl radicals include, without limitation,ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterms “alkenyl” embrace radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art. It is contemplated herein that alkenylradicals may be optionally substituted with various substituents, whereindicated.

The term “alkynyl”, alone or in combination, denotes linear or branchedradicals having at least one carbon-carbon triple bond and having two ormore carbon atoms. Examples of such radicals include, withoutlimitation, ehtynyl, propynyl (propargyl), butynyl, and the like. It iscontemplated herein that alkynyl radicals may be optionally substitutedwith various substituents, where indicated.

The term “halo”, alone or in combination, means halogens such asfluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, alone or in combination, embraces radicals whereinany one or more of the alkyl carbon atoms is substituted with halo asdefined above. For example, this term includes monohaloalkyl,dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl. Amonohaloalkyl radical, for example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroetbyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “hydroxyalkyl”, alone or in combination, embraces linear orbranched alkyl radicals having one or more carbon atoms any one of whichmay be substituted with one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl.

The term “alkoxy”, alone or in combination, embraces linear or branchedoxy-containing radicals each having alkyl portions of alpha to betanumber of carbon atoms. For example, a C₁₋₁₀alkoxy radical indicates analkoxide having one to ten carbon atoms, arranged in a linear orbranched fashion, attached to an oxygen atom. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxyradicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “partially or fully saturated” as used herein, refers to amoiety, linear, branched or cyclic in nature, having no atom-atom doubleor triple bonds, and one or more atom-atom double or triple bonds,arranged such that wherein the structure is cyclic, the ring structureis not aromatic, as appreciated by those skilled in the art.

The term “fully unsaturated” as used herein, refers to a moiety havingdouble or triple bonds, arranged in a manner such that the structure isaromatic, as appreciated by those skilled in the art.

The term “aryl”, alone or in combination, means a carbocyclic aromaticmoiety containing one, two or even three rings wherein such rings may beattached together in a fused manner. Thus the term “aryl” embracesaromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl,anthracenyl, and indanyl. Said “aryl” group may have 1 to 3 substituentssuch as alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy andalkylamino, and the like. Phenyl substituted with —O—CH₂—O— forms anaryl benzodioxolyl substituent. Aryl as used herein, implies a fullyunsaturated ring.

The term “heterocycles” or “heterocyclic radicals”, alone or incombination, embraces saturated, partially saturated and unsaturatedheteroatom-containing ring radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. This term does not includerings containing —O—O—, —O—S— or —S—S— portions. Said “heterocycle” mayhave 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano,alkyl, ralkyl, oxo, alkoxy, amino and alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also referred to hereinas “heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]; and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms[e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl anddihydrobenzofuryl]. Examples of heterocyclic radicals include five toten membered fused or unfused radicals. Further examples of heteroarylradicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl,thiazolyl, oxazolyl, furyl, and pyrazinyl. Other examples of heteroarylradicals are 5- or 6-membered heteroaryl, containing one or twoheteroatoms selected from sulfur, nitrogen and oxygen, such as thienyl,furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinylradicals.

Examples of non-nitrogen containing heteroaryl include, withoutlimitation, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Examples ofsuch radicals include benzyl, diphenylmethyl and phenylethyl. The arylin said aralkyl may be additionally substituted with halo, alkyl,alkoxy, halkoalkyl and haloalkoxy.

The term “aminoalkyl” and “diaminoalkyl” embraces “N-alkylamino” and“N,N-dialkylamino”, respectively, where amino groups are independentlysubstituted with one alkyl radical and with two alkyl radicals,respectively. Suitable alkylamino radicals may be mono or dialkylaminosuch as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylaminoand the like.

The term “C₁₋₁₀alkyl-amino-” denotes amino groups, which have beensubstituted with one or two alkyl radicals, such as N-methylamino. Thealkylamino radicals may be further substituted on the alkyl portion ofthe radical.

The term “aryl-alkyl-amino-” or “aralkylamino” denotes amino groups,which have been substituted with one or two aryl-substituted-alkylradicals, such as benzyl-amino. The aralkyl-amino radicals may befurther substituted on the aryl or alkyl portion of the radical.

The term “heterocyclyl-alkyl-amino-” denotes amino groups, which havebeen substituted with one or two heterocyclyl-substituted-alkylradicals, such as piperidyl-methyl-amino. The heterocyclyl-alkyl-aminoradicals may be further substituted on the heterocycle or alkyl portionof the radical.

The term “heteroaryl-alkyl-amino-” or “heteroaralkylamino” denotes aminogroups, which have been substituted with one or twoheteroaryl-substituted-alkyl radicals, such as pyrimidyl-amino. Theheteroaralkyl-amino radicals may be further substituted on theheteroaryl or alkyl portion of the radical.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “cycloalkyl” includes saturated carbocyclic groups. Examples ofcycloalkyl groups include C₃-C₆ rings, such as compounds including,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Examples of cycloalkenyl groups include C₃-C₆ rings, such as compoundsincluding, without limitation, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s) but not excluding other elements.

The terms “Formula I”, “Formula II” and “Formula III” include any subformulas.

The present invention comprises processes for the preparation of acompound of Formulas I and II.

Also included in the family of compounds of Formulas I-III are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formulas I-III may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Suitable exemplary organic acids include, withoutlimitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, exampleof which are formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I-III include, without limitation, metallic salts such as saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc, or salts made from organic bases including primary, secondary,tertiary amines and substituted amines including cyclic amines such ascaffeine, arginine, diethylamine, N-ethyl piperidine, aistidine,glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine,piperazine, piperidine, triethylamine, trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I-III. When a basic group and anacid group are present in the same molecule, a compound of FormulasI-III may also form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes 1-9, wherein the substituents are asdefined for Formulas I-III, above, except where further noted. Thesynthetic methods described below are merely exemplary, and thecompounds of the invention may be synthesized by alternate routes asappreciated by persons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following: BSA bovine serum albumin Cs₂CO₃ cesiumcarbonate CHCl₃ chloroform DCM, MC dichloromethane, methylene chlorideDIBAL diisobutylaluminum hydride DIEA, (iPr)₂Net diisopropylethylamineDME dimethoxyethane DMF dimethylformamide DMAP 4-dimethylaminopyridineDMSO dimethylsulfoxide Et₂O diethyl ether EtOAc ethyl acetate FBS fetalbovine serum G, gm gram h, hr hour HBr hydrobromic acid HCl hydrochloricacid HOBt 1-hydroxybenzotriazole hydrate H₂ hydrogen H₂O₂ hydrogenperoxide HPLC high pressure liquid chromatography IPA, IpOH isopropylalcohol K₂CO₃ potassium carbonate MgSO₄ magnesium sulfate MeOH methanolN₂ nitrogen NaHCO₃ sodium bicarbonate NaOH sodium hydroxide NaH sodiumhydride Na₂SO₄ sodium sulfate NH₄Cl ammonium chloride NH₄OH ammoniumchloride PBS phospate buffered saline Pd/C palladium on carbon Pd(PPh₃)₄palladium(0)triphenylphosphine tetrakis Pd(OAc)₂ palladium acetate RTroom temperature TEA, Et₃N triethylamine TFA trifluoroacetic acid THFtetrahydrofuran

The biaryl ring system (3), including substituted or unsubstitutedpyridyl-pyridines (where ring C and D are both pyridines),pyridyl-pyrimidines (where one of rings C and D is a pyridine and theother is a pyrimidine), pyridyl triazines (where D is a triazine),pyrimidyl-pyrimidines and pyrimidyl-triazines (where ring D is atriazine) and generally referred to herein as the C-D ring portion ofthe compounds of Formulas I-III, can be prepared according to the methodgenerally described in Scheme 1. As shown, Suzuki coupling methodologyutilizing an aryl halide (1) where X is a halide such as iodide, bromideor chloride, and an aryl borinate (2) in the presence of palladium, suchas Pd(PPh₃)₄, and a weak base, such as a Na₂CO₃, K₂CO₃ or NaHCO₃ in apolar solvent such as DME can be used to synthesize compound (3). LG isa known leaving group, such as F or Cl. Similarly, other known arylcoupling methods, such as use of stannanes, zincates and copper couplingtechniques are also suitable to prepare compound (3).

In a similar manner, phenyl-pyridines, phenyl-pyrimidines andphenyl-triazine C-D rings of the compounds of Formulas I-III, can alsobe prepared according to the Suzuki or other metallation chemistrymethods, wherein the aryl borinate (2) is a desirably substituted phenylborinate, as described in Scheme 1.

Alternatively, amino-substituted pyridyl pyrimidines C-D ring systems(8) can be prepared according to the method shown in Scheme 2.

Chloro-nicotinic acid chlorides (4) can be treated with dimethylmalonatein the presence of a suitable base and MgCl to form intermediate (5).Compound (5) can be cyclized to form the hydroxyl-substitutedpyrimidyl-pyridine compound (6), in the presence of suitable base andformamidine acetate. Desirable amino-R¹ groups can be installed at the 3position of the 4,6-pyrimidine D-ring by simply treating compound (7)with a primary or secondary amine, having the desired substitution, withheat under conditions milder than those required to displace the pyridylchloride of compound (6). Further, compound (6) can be treated withp-toluene sulfonyl chloride, or other similar activating reagents torender the pyrimidine hydroxyl group into a suitable leaving group (LG)for displacement with a desired, sufficiently reactive nucleophile,including amines, sulfur, and oxygen nucleophiles. Also, compound (6)may be treated with a base sufficiently strong to deprotonate thehydroxyl proton in order to alkylate the hydroxyl group, thereby formingan ether, alkoxy moiety, and the like. Further, compound (6) can beconverted to the corresponding thiol utilizing reactions and techniquesknown in the art. This thiol (not shown 0 may then be converted tocorresponding thio-linked R¹ groups. In addition, compound (7) can betreated with ammonia to give the amino adduct, which then can bealkylated, acylated, or otherwise substituted with a desired group. Suchmethods are known to those skilled in the art, and are described inJerry March's Advanced Organic Chemistry, 4^(th) edition (1992), whichdisclosure is hereby incorporated by reference in its entirety.

The 2,4-regioisomer of the above pyridyl-pyrimidines can also be madeusing the following Scheme 3.

Compound (10) can be made by treating the acid chloride of compound (9a)(ring C) and converting it to the corresponding methyl ketone (9b)followed by treatment with dimethyl formamide dimethylacetal to obtainthe corresponding enaminone (9c). Then substituted guanidine HCl can betreated with a suitable base, such as sodium methoxide, for a timeperiod prior to exposing the guanidine mixture to the enaminone (9c) toform the pyridyl pyrimidine (10). This method allows desired R¹ groupsto be installed prior to ring closure. Care must be taken to restrictthe R¹ groups in this method to those, which would not interfere with orreact during formation of intermediates 9a-9c and also ring closure toform compound (10), as appreciated by persons of ordinary skill in theart.

Alternatively, compound (9c) can be treated with guanidine HCl in thepresence of NaOH in isopropanol to afford the corresponding3-amino-pyrimidine D ring (not shown, where R¹ is NH₂). The R¹ positionof this intermediated can be modified using reductive alkylation methodswith corresponding aldehydes, acylation methods, and other groups, bymethods appreciated by persons of ordinary skill in the art, to installthe desired groups at this position on the D ring of compounds ofFormulas I-III. Alternatively, the 3-aminopyrimidine may be converted to3-fluoropyrimidine with use of t-butyl nitrate and HF pyridine, and thefluoride then displaced with a desired R¹ group such as NH₂R, OR and SR.This latter technique may also be used to convert amino-triazines to thecorresponding fluoro-triazines.

Similarly, pyridyl-triazines C-D biaryl ring systems can be made usingthe method of Scheme 4.

In a manner similar to the method illustrated and described in Scheme 2,desirable amino-R¹ groups can be installed at the 3 position of atriazine D ring by treating compound (15) with a primary or secondaryamine, having the desired substitution, with heat under conditions lessstrenuous than required to displace the pyridyl chloride of compound(15).

The C-D ring portion of the compounds of Formulas I-III can be attachedto the B ring of compound (17 or 17a—see scheme 5 below) by a number ofconventional methods known in the art, as disclosed in March. Suitablemethods are illustrated in Schemes 5 and 6 below.

As shown in Scheme 5, compound (18 or 18a) comprising biaryl ethers andthiols (where L¹=O and S, respectively) can be prepared by reactingcompound (16) (where LG is a leaving group, such as a halide, like achlorine or bromine) with a nucleophilic phenyl compound (17) wherein L¹is a suitable nucleophile, such as OH or SH (Scheme 5), or NHR or NH₂(Scheme 6) or carbon nucleophile, sufficient to displace the chloridefrom ring C of compound (16). For example, phenols (L¹=O) and thiols(L¹=S) can be coupled with activated aryl chlorides to form the biarylethers and thiols (compound 18) using weak bases such as TEA, orinorganic bases such as Cs₂CO₃, in DMSO at elevated temperatures, suchas ranging form about 70° C. to about 130° C. Similarly, thistransformation can also be carried out in NMP at about 200° C. in amicrowave.

Anilines (compound 17 or 17a) can be coupled with activated arylchlorides (compound 16) to form biaryl anilines (compound 18 or 18a)using Pd catalysis or NEt₃•TFA under suitable conditions, which may ormay not require the input of heat.

Alternatively, and with reference to Scheme 2, where certain R¹ and/orR² groups hinder or limit the ability to couple ring C to ring B via thenucleophilic displacement method described above, the B-C ring couplingcan be effected from intermediate compound (6) in Scheme 2 as follows inScheme 7.

As shown, compound (16) can first be reacted with the desired B ringnucleophilic species prior to converting the D-ring hydroxyl group tothe corresponding chloride for subsequent displacement with an amine, orother desired R¹⁵ group.

Compounds of the invention (Formulas I-III) wherein C¹ is CR¹⁰ can beprepared by the general method shown in Scheme 8.

As shown, commercially available 2-hydroxynicotinic acid can beiodinated and subjected to thionyl chloride according to the proceduredisclosed in Elworthy et al., J. Med. Chem., 40(17):2674-2687 (1997),which disclosure is incorporated herein by reference in its entirety.Conversion of the iodinated intermediate (compound 22) to thecorresponding pyrimidine (compound 23) proceeds as described above inScheme 2. After displacement of the pyridyl chloride (compound 23) withan aniline (compound 17) to form compound (24), Pd(0) mediated-couplingwith an aryl boronate in the presence of mild base, such as sodium orpotassium carbonate or bicarbonate, in toluene affords compound (25), anaryl pyridyl pyrimidine. Compound (25) can also be prepared usingcorresponding stannanes or zincates, as known in the art. Alternatively,desired R¹⁰ groups may be installed onto the C-ring via the iodide,using conventional methods (not shown), as appreciated by those skilledin the art.

Alternatively, the desired aryl group can be installed on ring C(compound 20) even before building the D-C ring piece of compounds ofFormulas I-III. For example, Church et al. describes the synthesis of5-aryl-2-chloropyridines from phenylacetic acids in J. Org. Chem.,60:3750-3758 (1995), which disclosure is incorporated herein byreference in its entirety.

The following examples represent methods of synthesizing or preparingdesired compounds of Formulas I-III and various structural moieties ofthe compounds. It should be appreciated that these examples are forillustrative purposes only and are not to be construed as limiting thescope of this invention in any manner. It should also be appreciatedthat other conventional, known or developed alternative methods may alsobe utilized to prepare compounds of Formulas I-III.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (AcCN/0.1% TFA) with a 11 min gradient from 5% to100% AcCN. The gradient was followed by a 2 min return to 5% AcCN andabout a 2.5 minute re-equilibration (flush).

LC-MS Method:

Samples were run on a Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈ (3.5μ) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (AcCN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation with a 20×50 mm column at 20 nL/nmin.The mobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solventB (AcCN/0.1% TFA) with a 10 min gradient from 5% to 100% solvent B. Thegradient is followed by a 2 min return to 5% AcCN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz or on a Bruker 400 MHz instrument. Where socharacterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

EXAMPLE 1 Synthesis of 4-(1-methyl-4-phenyl-1H-imidazol-2-ylamino)phenolStep 1: 1-methyl-4-phenyl-1H-imidazole

To a slurry of sodium hydride, 60% in mineral oil (1.2 g, 31 mmol) in100 mL anhyd. THF at 0° C. was added 4-phenylimidazole (4.00 g, 28 mmol)in small portions under nitrogen. Upon complete addition, the reactionwas homogeneous and orange. After 10 min, methyl iodide (2.1 ml, 33mmol) was added and the reaction was allowed to warm to ambienttemperature. After 2 h, the reaction was quenched with 10 mL water andconcentrated in vacuo. The resulting liquid was partitioned betweenwater/brine and DCM. The aqueous layer was extracted with DCM (4×). Thecombined organic extracts were dried over anhyd sodium sulfate,filtered, and concentrated in vacuo to give an orange solid. This wasdissolved in dichloromethane and purified by silica gel chromatography,120 g, 60 min, 0-50% 90/10 DCM/MeOH in DCM, to give1-methyl-4-phenyl-1H-imidazole and 1-methyl-5-phenyl-1H-imidazole asoff-white solids.

Step 2: 2-chloro-1-methyl-4-phenyl-1H-imidazole

To a solution of 1-methyl-4-phenyl-1H-imidazole (0.600 g, 3.79 mmol) in15 mL THF at −78° C. under nitrogen was added n-butyllithium 2.5 M inhexanes (1.67 ml, 4.17 mmol) dropwise over 3 min. The resultingorange-brown solution was allowed to stir for 30 min, at which time asolution of hexachlorethane (0.988 g, 4.17 mmol) in 5 mL THF was addedslowly down the side of the flask. The orange-brown solution was allowedto stir for 1 h, and was quenched with sat'd aq. NH₄Cl, warmed toambient temperature, and stirred overnight. The mixture was extractedwith EtOAc, the organic layers collected and dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give2-chloro-1-methyl-4-phenyl-1H-imidazole as a brown solid. MS m/z=193[M+H]⁺. Calc'd for C₁₀H₉N₂Cl: 192.6.

Step 3: 4-(1-methyl-4-phenyl-1H-imidazol-2-ylamino)phenol

A slurry of 4-aminophenol (0.227 g, 2.08 mmol),2-chloro-1-methyl-4-phenyl-1H-imidazole (0.400 g, 2.08 mmol), andp-toluenesulfonic acid monohydrate (0.395 g, 2.08 mmol) was heated in2.5 mL 2-BuOH in a sealed tube to about 110° C. for 24 h. Thetemperature was increased to about 120° C. and the solution was heatedfor 24 h. The reaction was cooled and partitioned between 50 mL pH7buffer and DCM. The aqueous layer was extracted with DCM (3×), and thecombined organics were dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. The resulting brown oil was purified bysilica gel chromatography (0-100% 90/10 DCM/MeOH in DCM) to give4-(1-methyl-4-phenyl-1H-imidazol-2-ylamino)phenol as a tan solid. MSm/z=266 [M+H]⁺. Calc'd for C₁₆H₁₅N₃O: 265.3.

EXAMPLE 2 Synthesis of N1-(2-(dimethylamino)ethyl)benzene-1,2-diamineStep 1: N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine

To a mixture of 2-fluoronitrobenzene (2.0 g, 14 mmol) and sodiumbicarbonate (5.9 g, 71 mmol) in 30 mL THF under nitrogen was added N1,N1-dimethylethane-1,2-diamine (1.7 mL, 16 mmol). The reaction wasallowed to stir at ambient temperature for 3 h, and then a water-cooledreflux condenser was added and the mixture was heated to 70° C. for 16h. The reaction was cooled to ambient temperature, filtered throughpaper, and concentrated in vacuo to giveN-(2-(dimethylamino)ethyl)-2-nitrobenzenamine as a yellow oil. Thismaterial was used without further purification.

Step 2: N1-(2-(dimethylamino)ethyl)benzene-1,2-diamine

N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine (2.0 g, 14 mmol) and 10%palladium on carbon, wet, 50% water (3.0 g) were combined undernitrogen. 30 mL MeOH was added via syringe, and the atmosphere wasreplaced with hydrogen from a balloon. The reaction was stirred rapidlyfor 20 h, at which point the reaction was flushed with nitrogen, andfiltered through a pad of Celite®, and concentrated in vacuo to giveN1-(2-(dimethylamino)ethyl)benzene-1,2-diamine as a red-brown solid.This material was used without further purification. MS m/z=180 [M+H]⁺.Calc'd for C₁₀H₁₇N₃: 179.3.

EXAMPLE 3 Synthesis of N1-(3-(dimethylamino)propyl)benzene-1,2-diamine

The title compound was synthesized in a manner analogous to thatdescribed in Example 2. MS m/z=194 [M+H]⁺. Calc'd for C₁₁H₁₉N₃: 193.3.

EXAMPLE 4 (Method A)

Synthesis ofN-(6-(3-(2-(methylamino)pyrinidin-4-yl)pyridin-2-yloxy)pyridin-3-yl)-1H-benzo[d]imidazol-2-amineStep 1: 4-(2-(4-isothiocyanatophenoxy)phenyl)-N-methylprimidin-2-amine

To a slurry of 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine(0.300 g, 1.03 mmol) in MC was added di-2-pyridyl thionocarbonate (0.227g, 0.977 mmol). The orange reaction was allowed to stir overnight, andwas then diluted with MC and washed 4×H₂O. The organic layer was driedover anhyd. Na₂SO₄, filtered, and concentrated in vacuo to give4-(2-(4-isothiocyanatophenoxy)phenyl)-N-methylpyrimidin-2-amine as anoff-white solid. This material was used without further purification. MSm/z=335 [M+H]⁺. Calc'd for C₁₈H₁₄N₄OS: 334.4.

Step 2:N-(6-(3-(2-(methylamino)pirimidin-4-yl)pyridin-2-yloxy)pyridin-3-yl)-1H-benzo[d]imidazol-2-amine

A mixture of benzene-1,2-diamine (0.091 g, 0.85 mmol),4-(2-(5-isothiocyanatopyridin-2-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine(0.237 g, 0.70 mmol), and polymer-supported carbodiimide (Argonauttechnologies, 1.6 mmol/g, 1.3 g, 2.1 mmol) was heated for 14 h inanhydrous THF in a sealed vial. The reaction was cooled and wasfiltered, rinsing with 100 mL DCM. The filtrate was concentrated invacuo to give an off-white solid. Sonication in dichloromethane gave afluffy precipitate, which was filtered and collected to give anoff-white solid. This material was adsorbed onto 0.8 g SiO2 fromMeOH/MC, and purified by silica gel chromatography, 40 g, 0-10% MeOH/MCto giveN-(6-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-3-yl)-1H-benzo[d]imidazol-2-amineas a white solid MS m/z=411 [M+H]⁺. Calc'd for C₂₂H₁₈N₈O: 410.4.

EXAMPLE 5 (Method B1)

Synthesis of4-(2-(4-(5-phenyl-1,3,4-thiadiazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine

A slurry of pyridinium p-toluenesulfonate (0.18 g, 0.72 mmol),4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.100 g, 0.36mmol), and 2-chloro-5-phenyl-1,3,4-thiadiazole (0.077 g, 0.39 mmol;prepared by method described in J. Med. Chem., 31:902 (1988)) was heatedin 2 mL 2-BuOH in a sealed tube to 110° C. The reaction became darkbrown and homogeneous. After 2 h the reaction was quenched with 1N NaOHand DCM. The aqueous layer was extracted 2×DCM, and the emulsifiedaqueous layer was filtered and rinsed with dichloromethane. Theresulting solid was adsorbed onto silica gel from MeOH/DCM, dried, andpurified by silica gel chromatography, 0-100% 90/10 DCM/MeOH in DCM togive4-(2-(4-(5-phenyl-1,3,4-thiadiazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a white solid. MS m/z=440 [M+H]⁺. Calc'd for C₂₃H₁₇N₇OS: 439.5.

EXAMPLE 6 (Method B2)

Synthesis of4-(2-(4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineStep 1: 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole

To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-thiol (2.00 g, 10mmol) in NaOH 1.0 M in H₂O (21 ml, 21 mmol) was added a solution of CH₃I(0.98 mL, 16 mmol) in 6 mL EtOH. The reaction became cloudy and thenclear. After 15 min, a white solid precipitated out of the reaction. Thereaction was filtered, rinsing with water. The solid was collected anddried in vacuo to give4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole as a white solid. MSm/z=206 [M+H]⁺. Calc'd for C₁₀H₁₁N₃S: 205.3.

Step 2: 4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole

A slurry of 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole (0.360 g,1.75 mmol) and oxone(r) monopersulfate compound (2.16 g, 3.51 mmol) werestirred rapidly in 5 mL MeOH overnight. The reaction was concentratedand the solids diluted with water, ice, and treated with 6 N NaOH untila pH>10. The resulting material was extracted 3×DCM, and the combinedorganic layers were dried over anhyd sodium sulfate, filtered, andconcentrated to give4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole as a white solid.MS m/z=238 [M+H]⁺. Calc'd for C₁₀H₁₁N₃O₂S: 237.3.

Step 3:4-(2-(4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine

To a slurry of 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine(0.150 g, 0.54 mmol) and4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole (0.14 g, 0.59mmol) in 0.6 mL THF was added lithium bis(trimethylsilyl) amnide, 1.0 msolution in tetrahydrofuran (1.1 ml, 1.1 mmol). The reaction became asolid, and was sealed and heated to 70° C., at which point it became aheterogeneous brown mixture that could be stirred. After 2 h, thereaction did not appear to make further progress. The reaction wasquenched with sat'd aqueous NH₄Cl and partitioned between DCM and water.The aqueous layer was extracted 1×DCM. The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The material was absorbeded onto silica gel from MeOH/DCM anddried. The residue was purified by silica gel chromatography, 40 g(0-100% 90/10 DCM/MeOH in MC) to give4-(2-(4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a white solid. MS m/z=437 [M+H]⁺. Calc'd for C₂₄H₂₀N₈O: 436.5.

EXAMPLE 7 (Method B3)

Synthesis ofN-(3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzo[d]oxazol-2-amine

To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (30 mg,0.11 mmol) in toluene (2.0 mL) was added 2-chlorobenzo[d]oxazole (0.014mL, 0.12 mmol). The resulting mixture was heated to 100° C. for 47 h.The mixture was diluted with DMSO and purified by Gilson reverse-phaseHPLC. The product-containing fractions were combined, diluted withmethylene chloride, and extracted with saturated sodium carbonate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated to yield the title compound as a tan solid. MS m/z=396[M+H]⁺. Calc'd for C₂₃H₁₇N₆O₂: 395.42.

EXAMPLE 8 (Method C)

Synthesis ofN-methyl-4-(2-(4-(5-methyl-4-phenyl-1H-imidazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineStep 1:1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-t-butylcarbamate

To a dark solution of4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.750 g,2.6 mmol) in DMF was added TEA (1.1 ml, 7.9 mmol) and1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.78 g, 2.7mmol) followed by mercury(ii) chloride (0.80 g, 2.9 mmol). Upon additionof the mercury, the reaction became very thick and difficult to stir.The reaction was allowed to stir overnight, and was then diluted withDCM and 2 N sodium carbonate solution. The mixture was filtered througha 2 cm Celite® pad in a glass frit, rinsing with water anddichloromethane. The organic layer was washed three times with water,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresulting brown oil was purified by silica gel chromatography, 80 g,0-30% 90/10 MC/MeOH in MC, to give1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-t-butylcarbamate as a peach-colored solid. MS m/z=536 [M+H]⁺. Calc'dfor C₂₇H₃₃N₇O₅: 535.6.

Step 2:1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-TFA salt

To an orange solution of1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-t-butylcarbamate (1.1 g, 2.1 mmol) in 15 mL DCM under nitrogen at 0°C. was added TFA (3.1 ml, 41 mmol). The reaction was allowed to warm toambient temperature and was allowed to stir overnight. The reaction wasconcentrated in vacuo to give1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-TFA salt as a brown oil, which was used without furtherpurification. MS m/z=336 [M+H]⁺. Calc'd for C₁₇H₁₇N₇O: 335.2.

Step 3:N-methyl-4-(2-(4-(5-methyl-4-phenyl-1H-imidazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine

To a mixture of1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidinebis-TFA salt (0.200 g, 0.35 mmol) and potassium carbonate (0.20 g, 1.4mmol) in 1 mL DMSO was added 2-bromo-1-phenylpropan-1-one (0.054 ml,0.35 mmol). The reaction was allowed to stir at ambient temperature for30 min, then 70° C. After 16 h, the reaction was quenched by addition ofwater and was-extracted with EtOAc. The organic layer was dried overanhyd. Sodium sulfate, filtered, and concentrated in vacuo. Theresulting green/brown oil was purified by silica gel chromatography (40g, 0-100% 90/10 MC/MeOH in MC) to give an oil. This was lyophilized fromMeOH/water to giveN-methyl-4-(2-(4-(5-methyl-4-phenyl-1H-imidazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineas an off-white solid. MS m/z=450 [M+H]⁺. Calc'd for C₂₆H₂₃N₇O: 449.5.

EXAMPLE 9 (Method D)

Synthesis ofN-methyl-4-(2-(4-(5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineStep 1:1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothiourea

To a heterogeneous brown mixture of4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.260 g,0.886 mmol) in 2 mL acetone was added benzoyl isothiocyanate (0.136 ml,0.975 mmol) dropwise via syringe. The mixture became homogeneous andremained brown. After 10 min, a precip formed. After 16 h, iodomethane(0.0554 ml, 0.886 mmol) was added, and the reaction was heated to 80° C.The mixture became homogeneous. After 3 h, further iodomethane (0.0554ml, 0.886 mmol) was added and after 1 h at 80° C. and 3 days at ambienttemperature, the reaction was adsorbed onto 1.7 g SiO₂ and dried. Thesolid was purified by silica gel chromatography, 40 g, 0-10% MeOH/MC, togive1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothioureawhich was used without further purification. MS m/z=471 [M+H]⁺. Calc'dfor C₂₅H₂₂N₆O₂: 470.5.

Step 2:N-methyl-4-(2-(4-(5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine

A slurry of1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothiourea(0.174 g, 0.37 mmol) and anhydrous hydrazine (0.35 ml, 11 mmol) in EtOHwas sealed and heated to 80° C. After 16 h, a yellow precipitate formed.The reaction was cooled to ambient temperature, filtered, rinsing with2×1 mL EtOH, and the solid was dried in vacuo to giveN-methyl-4-(2-(4-(5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a white solid. MS m/z=437 [M+H]⁺. Calc'd for C₂₄H₂₀N₈O: 436.5.

EXAMPLE 10 (Method E)

Synthesis of4-(2-(4-(4-methyl-1-phenyl-1-H-pyrazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineStep 1. Preparation ofN-(4-methoxyphenal)-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-amine

A 100 ml round bottom flask was charged with4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-ol (1.00 g, 5.68 mmol),4-methoxybenzenamine (2.27 g, 18.44 mmol), and p-toluenesulfonic acidmonohydrate (0.59 g, 3.12 mmol). The reaction mixture was stirred at140° C. under a nitrogen atmosphere for 16 h. The reaction was cooledand dissolved in 1% NaOH solution and ether. The organic layer wasseparated, washed with 1% HCl solution and water, then dried overNa₂SO₄, filtered, and concentrated to affordN-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1-H-pyrazol-3-amine asa brown solid. MS m/z=282.2 [M+H]⁺. Calc'd for C₁₇H₁₉N₃O: 281.35.

Step 2. Preparation ofN-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine

A 200 ml round bottom flask, under nitrogen, was charged withN-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-amine(0.85 g, 3.02 mmol) and DCM (60.42 ml, 0.05 M). To this solution wasadded slowly manganese dioxide (0.58 g, 6.65 mmol). Reaction stirred atRT under a nitrogen atmosphere for 16 h. The reaction mixture wasdiluted with DCM and filtered over Celite®. The filtrate wasconcentrated to afford brown oil, which was purified by ISCO silica gelchromatography (20-40% EtOAc/hexanes) to affordN-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine. MS m/z=280.2[M+H]⁺. Calc'd for C₁₇H₁₇N₃O: 279.34.

Step 3. Preparation of 4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol

A 50 ml round bottom flask was charged withN-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine (0.37 g, 1.33mmol), hydrobromic acid (2.16 ml, 39.74 mmol), and acetic acid (2.27 ml,39.74 mmol). The reaction mixture was stirred at 110° C. for 4 h, thencooled to RT and diluted with water. The solution was neutralized with 6N NaOH until a pH of about 6, upon which the product precipitated out ofsolution. The solid was filtered and dried under high vacuum to afford4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol as a dark solid. MSm/z=266.1 [M+H]⁺. Calc'd for C₁₆H₁₅N₃O: 265.31.

Step 4. Preparation of4-(2-(4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine

A resealable reaction tube was charged with4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol (0.12 g, 0.45 mmol),4-(2-chloropyridin-3-yl)pyrimidin-2-amine (0.09 g, 0.45 mmol), cesiumcarbonate (0.30 g, 0.91 mmol), and DMSO (2.26 ml, 0.2 M). The reactionvessel was sealed and the mixture stirred at 130° C. for 16 h. Thereaction was cooled to RT, diluted with 1 ml DMSO and passed through aPTFE acrodisc filter via syringe. The residue was purified by Gilsonreverse phase chromatography (10% to 90% CH₃CN/H₂O/0.1% TFA), and theproduct-containing fractions were combined, basified by addition of aq.NaHCO₃ and extracted with ethyl acetate. The organic portion was driedwith Na₂SO₄, filtered, and concentrated to afford pure4-(2-(4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a tan solid. MS m/z=436.2 [M+H]⁺. Calc'd for C₂₅H₂₁N₇O: 435.48.

EXAMPLE 11 (Method F1)

Synthesis of5,6-difluoro-N-(4-(3-(2-(3-(4-methylpiperazin-1-yl)propylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineStep 1. Preparation of4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine

A resealable pressure bottle was charged with4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (2.85 g, 12.00 mmol),4-aminophenol (1.44 g, 26.5 mmol), and cesium carbonate (1.44 g, 13.20mmol). These reagents were suspended in DMSO (24 ml, 0.50 M), and thevessel was sealed and mixture heated to 130° C. for 48 h. The reactionmixture was allowed to cool to RT, diluted with water and extracted withethyl acetate. The organic layer was collected, dried with Na₂SO₄,filtered, and concentrated to give light brown residue, which waspurified by silica gel chromatography (ISCO, 10% to 50% EthylAcetate/Hexanes) to afford4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine as alight yellow solid. MS m/z=311 [M+H]⁺. Calc'd for C₁₆H₁₄N₄OS: 310.37.

Step 2. Preparation of4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine

A dry 100 ml round bottom flask, under nitrogen, was charged with4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy) benzenamine (1.72 g,5.54 mmol), O,O-dipyridin-2-yl carbonothioate (1.35 g, 5.82 mmol), andDCM (37 ml, 0.15 M). The vessel was closed, kept under nitrogen, andmixture stirred at RT for 18 h. The reaction was diluted with 20 ml DCMand washed with water. The organic layer was collected, dried withNa₂SO₄, filtered, and concentrated to give4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine asa yellow solid. MS m/z=353.0 [M+H]⁺. Calc'd for C₁₇H₁₂N₄OS₂: 352.43.

Step 3. Preparation of5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

A resealable pressure vial, under nitrogen, was charged with4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine(1.12 g, 3.18 mmol), PS-DCC (1.27 mmol/g polymer supported cyclohexylcarbodiimide) (7.50 g, 9.53 mmol), 4,5-difluorobenzene-1,2-diamine (0.69g, 4.77 mmol), and THF (45 ml, 0.07 M). The vessel was sealed and thereaction mixture stirred at 70° C. for 4 h. The reaction mixture wascooled to RT, diluted with DCM, and filtered over celite. The filtratewas concentrated to afford yellow residue, which was triturated withDCM, filtered, and dried under high vaccuum to afford5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineas a tan solid. MS m/z=463.1 [M+H]⁺. Calc'd for C₂₃H₁₆F₂N₆OS: 462.48.

Step 4. Preparation of5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

A 100 ml dry round bottom flask was charged with5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine(0.82 g, 1.76 mmol) and sonicated in methanol (17.62 ml, 0.10 M) for 20minutes. To this was added oxone (3.25 g, 5.29 mmol) and mixture stirredat RT for 2 days. The reaction mixture was cooled to 0° C. and basifiedwith aq. NaHCO₃. The resulting solids were filtered, washed with water,and dried under high vacuum to provide5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineas a light yellow solid. MS m/z=495.1 [M+H]⁺. Calc'd for C₂₃H₁₆F₂N₆O₃S:494.47.

Step 5. Preparation of5,6-difluoro-N-(4-(3-(2-(3-(4-methylpiperazin-1-yl)propylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

A resealable pressure vial was charged with5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine(0.14 g, 0.28 mmol), 3-(4-methylpiperazin-1-yl)propan-1-amine (0.18 g,1.13 mmol), and 2-propanol (1.89 ml, 0.15 M). The reaction vessel wassealed and the mixture stirred at 70° C. for 16 h. The reaction mixturewas cooled to RT, diluted with DCM, and washed with Aq. NaHCO₃. Theorganic layer was collected, dried over Na₂SO₄, and concentrated toafford brown residue, which was purified by Gilson reverse phasechromatography (10% to 90% CH₃CN/H₂O/0.1% TFA). The product-containingfractions were combined, basified by addition of aq. NaHCO₃ andextracted with ethyl acetate. The organic portion was dried with Na₂SO₄,filtered, and concentrated to afford pure5,6-difluoro-N-(4-(3-(2-(3-(4-methylpiperazin-1-yl)propylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineas a yellow solid. MS m/z=572.2 [M+H]⁺. Calc'd for C₃₀H₃₁F₂N₉O: 571.62.

EXAMPLE 12 (Method F2)

Synthesis of5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1-H-benzo[d]imidazol-2-amine

A resealable pressure bottle, under nitrogen, was charged with5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine(0.13 g, 0.26 mmol), 4-(4-methylpiperazin-1-yl)benzenamine (0.25 g, 1.31mmol), TFA (0.12 ml, 1.58 mmol), and 2-propanol (10.00 ml, 0.03 M). Thereaction vessel was sealed and the mixture stirred at 90° C. for 4 days.The reaction mixture was cooled to RT and concentrated to brown residue.The residue was purified by Biotage silica gel chromatography (2%-8%MeOH/Dichloromethane) followed by Gilson reverse phase chromatography(10% to 90% CH₃CN/H₂O/0.1% TFA). The product-containing fractions werecombined, basified by addition of aq. NaHCO₃ and extracted with ethylacetate. The organic portion was dried with Na₂SO₄, filtered, andconcentrated to afford5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineas a yellow solid. MS m/z=606.1 [M+H]⁺. Calc'd for C₃₃H₂₉F₂N₉O: 605,64.

EXAMPLE 13 (Method F3)

Synthesis of5,6-difluoro-N-(4-(3-(2-(pyridin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

A resealable reaction vial, under nitrogen, was charged withpyridin-3-amine (0.04 g, 42.50 mmol) and DMF (0.80 ml, 0.1 M). This wascooled to 0° C. and 60% wt in oil sodium hydride added (0.01 g, 42.50mmol). The reaction mixture was stirred at 0° C. under a nitrogenatmosphere for 35 min.5,6-Difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine(0.04 g, 0.08 mmol) was added slowly to the mixture which was allowed towarm up to RT and stirred for 1 hr. The reaction mixture was heated to60° C. and stirred for 1 hr. The reaction mixture was cooled to RT, thendiluted with water and ethyl acetate. The layers were separated, theorganic layer was dried over sodium sulfate and concentrated underreduced pressure to give oily residue, which was purified by silica prepplate (0.5% NH₄OH/9.5% MeOH/Dichloromethane) followed by Gilson reversephase chromatography (10% to 90% CH₃CN/H₂O/0.1% TFA) to afford5,6-difluoro-N-(4-(3-(2-(pyridin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amineas a yellow solid. MS m/z=509.0 [M+H]⁺. Calc'd for C₂₇H₁₈F₂N₈O: 508.48.

EXAMPLE 14

Synthesis of6,7-difluoro-N-(5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amineStep 1:4-(2-(6-chloropyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine

A mixture of cesium carbonate (5.03 g, 15.4 mmol), 6-chloropyridin-3-ol(1.00 g, 7.72 mmol), and4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (1.83 g, 7.72 mmol)was sealed and heated to 120° C. overnight. The reaction was cooledslightly and poured slowly into a rapidly stirring solution of 250 mLwater. A tan precipitate resulted which was collected by filtrationthrough a 0.45 micron filter. The solid was washed 3× with water, thendried in vacuo overnight to give4-(2-(6-chloropyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine asa tan solid. MS m/z=331 [M+H]⁺. Calc'd for C₁₅H₁₁ClN₄OS: 330.8.

Step 2:5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine

To a brown solution of tris(dibenzylideneacetone)dipalladium (o) (0.68g, 0.75 mmol), 2-(dicyclohexylphosphino)biphenyl (0.50 g, 1.4 mmol), and4-(2-(6-chloropyridin-3-yloxy) pyridin-3-yl)-2-(methylthio)pyrimidine(1.9 g, 5.7 mmol) in 15 mL dioxane was added solid lithiumbis(trimethylsilyl) amide (2.9 g, 17 mmol). Argon was bubbled throughthe reaction for 1 min, and then it was sealed and heated to 65° C. for3.5 days. The reaction was cooled to ambient temperature, diluted withwater, and acidified to a pH of about 1 with stirring, then brought topH of about 5 with 6N NaOH. Dichloromethane was added and reaction wasfiltered through 2 cm Celite® in a frit, rinsing with MC and water. Thelayers were separated, and the organic layer was dried over anhyd.Na₂SO₄, filtered, and concentrated in vacuo. The material was diluted in100 mL MC, and extracted 3×100 mL 1 N HCl. The aqueous layers werecooled to 0° C. and basified with 6 N NaOH to about pH of 10. Theaqueous layer was extracted 3×100 mL with MC. The organic layers werecombined, dried over anhdrous sodium sulfate, filtered, and concentratedin vacuo to a brown oil. The oil residue was purified by silica gelchromatography, 120 g, 0-50% MC-90/10 MC/MeOH, to afford5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine as ayellow solid. MS m/z=312 [M+H]⁺. Calc'd for C₁₅H₁₃N₅OS: 311.4.

Step 3:4-(2-(6-isothiocyanatopyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine

To a mixture of5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine(0.170 g, 0.546 mmol) in DCM was added di-2-pyridyl thionocarbonate(0.133 g, 0.573 mmol). The reaction was allowed to stir overnight. After16 h, the reaction was washed 4× with water, then transferred to aseparatory funnel and diluted with DCM. The organic layer was washedwith water, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give4-(2-(6-isothiocyanatopyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine.MS m/z=354 [M+H]⁺. Calc'd for C₁₆H₁₁N₅OS₂: 353.4.

Step 4:6,7-difluoro-N-(5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine

A mixture of4-(2-(6-isothiocyanatopyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine(0.205 g, 0.580 mmol), 3,4-difluorobenzene-1,2-diamine (0.100 g, 0.696mmol), and polymer-supported carbodiimide (1.34 g, 1.74 mmol, 1.3mmol/g) in THF was heated in a sealed vial. After 4 h, the reaction wascooled slightly and filtered, rinsing with 100 mL DCM. The filtrate wasconcentrated in vacuo to give 0.280 g yellow solid. 6 mL MeOH was addedto the solid and the slurry sonicated for 2 min. The slurry wasfiltered, and the solid rinsed 1×1 mL MeOH, 1×1 mL diethyl ether, anddried in vacuo to give6,7-difluoro-N-(5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amineas a light yellow solid. MS m/z=464 [M+H]⁺. Calc'd for C₂₂H₁₅F₂N₇OS:463.4.

Step 5: give6,7-difluoro-N-(5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine

To a slurry of6,7-difluoro-N-(5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine(0.179 g, 0.39 mmol) in methanol was added oxone(r) (0.65 ml, 1.2 mmol).The reaction was allowed to stir at ambient temperature for 5 h. 1Equivalent of Oxone was added and the reaction was stirred overnight. 2mL MeOH and 3 equivalents of Oxone that was finely powdered with amortar and pestle was added to the reaction, which was stirred foranother 24 h. The reaction was concentrated to ½ volume, water wasadded, and the pH basified with 6 N NaOH at 0° C. The mixture wasfiltered, and the solid rinsed with water and methanol. The solid wasdried in vacuo, and the solid was suspended in 10% MeOH/MC and filteredthrough a 1 cm plug of silica gel in a frit, eluting with 50 mL 10%MeOH/MC, and concentrated to give a brown solid that was a mixture of6,7-difluoro-N-(5-(3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amineand6,7-difluoro-N-(5-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-aminethat was used directly in the next reaction.

The mixture of6,7-difluoro-N-(5-(3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amineand6,7-difluoro-N-(5-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine(0.140 g, 0.28 mmol) in methylamine, 2.0 M solution in THF (2.1 ml, 4.2mmol) was heated in a sealed tube to 70° C. After 4 h, the reaction waspartitioned between EtOAc and 1 N NaOH, and the aqueous suspension wasextracted 1×EtOAc, 3× dichloromethane, and the suspension was thenfiltered and rinsed with methanol. The solid material was combined withthe combined organic layers adsorbed onto 2 g silica gel and purifiedwith silica gel chromatography, eluting with 0-75% MC-90/10 MC/MeOH togive a white solid. The solid was sonicated in methanol and filtered,rinsing with Et₂O. The resulting material was dried in vacuo to give6,7-difluoro-N-(5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amineas a white solid. MS m/z=447 [M+H]⁺. Calc'd for C₂₂H₁₆F₂N₈O: 446.4.

The following compounds exemplified in Table I were made using variousof the Methods A, B1-B3, C, D, E and F1-F3 described in the examplesabove. TABLE I Ex. No. Compound Name MS (M + H⁺) Method 15N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 460 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 16N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 528 Apyridinyl)oxy)-1-naphthalenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine 17 N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2-461 A pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 18N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 461 Apyridinyl)oxy)-1-naphthalenyl)-1,3-benzoxazol-2-amine 19N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 477 Apyridinyl)oxy)-1-naphthalenyl)-1,3-benzothiazol-2-amine 205,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 496 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 214-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 474 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 22N-(4-((3-(2-((2-(4-morpholinyl)ethyl) amino)-4- 559 Apyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine23 6-chloro-5-fluoro-N-(4-((3-(2-(methylamino)-4- 512 Apyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine24 N-(4-((3-(2-(methylsulfanyl)-4-pyrimidinyl)-2- 477 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 25N˜1˜-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1- 517 F1naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N˜2˜,N˜2˜-dimethyl-1,2-ethanediamine 26N˜1˜-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1- 531 F1naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N˜3˜,N˜3˜-dimethyl-1,3-propanediamine 27N-(4-((3-(2-(methylsulfonyl)-4-pyrimidinyl)-2- 509 F1pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 285,7-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 496 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 29N˜1˜-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1- 545 F1naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N˜4˜,N˜4˜-dimethyl-1,4-butanediamine 30N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 596 Apyridinyl)oxy)-1-naphthalenyl)-5,7-bis(trifluoromethyl)-1H-benzimidazol-2-amine 31 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-461 A pyridinyl)oxy)-1-naphthalenyl)-3H-imidazo[4,5-b]pyridin- 2-amine32 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 461 Apyridinyl)oxy)-1-naphthalenyl)-3H-imidazo[4,5-c]pyridin- 2-amine 331-(3-(dimethylamino)propyl)-N-(4-((3-(2-(methylamino)- 545 A4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine34 1-(2-(dimethylamino)ethyl)-N-(4-((3-(2-(methylamino)-4- 531 Apyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine35 N-(4-((3-(2-((3-(1-pyrrolidinyl)propyl) amino)-4- 557 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine36 N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 474 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 37N-(3,5-dichloro-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 478 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 38N-1H-benzimidazol-2-yl-8-((3-(2-(methylamino)-4- 461 Apyrimidinyl)-2-pyridinyl)oxy)-5-quinolinamine 394,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 461 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 406,7-difluoro-N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2- 447 Apyridinyl)oxy)-3-pyridinyl)-1H-benzimidazol-2-amine 41N-(4-((2-(2-(methylamino)-4- 409 Apyrimidinyl)phenyl)oxy)phenyl)-1H-benzimidazol-2- amine 426,7-difluoro-N-(4-((2-(2-(methylamino)-4- 445 Apyrimidinyl)phenyl)oxy)phenyl)-1H-benzimidazol-2- amine 432-((4-(1H-benzimidazol-2-ylamino) phenyl)oxy)-N- 409 Amethyl-3,4′-bipyridin-2′-amine 442-((4-((6,7-difluoro-1H-benzimidazol-2- 445 Ayl)amino)phenyl)oxy)-N-methyl-3,4′-bipyridin-2′-amine 45N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3- 460 Amethyl-1-naphthalenyl)-1H-benzimidazol-2-amine 46N-(4-((3-(2-((2-(1-methyl-2-pyrrolidinyl)ethyl)amino)-4- 557 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine47 5,7-dimethyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 486-methyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2- 410 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 495-methyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2- 410 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 504-methyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2- 410 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 51N-(4-((3-(2-(((1-ethyl-4-piperidinyl) methyl)amino)-4- 571 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine52 N-(4-((3-(2-((1-methyl-4-piperidinyl) amino)-4- 543 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine53 4,5-difluoro-N-(4-((3-(1H-pyrazol-4-yl)-2- 405 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 54N-(4-((3-(1H-pyrazol-4-yl)-2-pyridinyl) oxy)phenyl)-1H- 369 Abenzimidazol-2-amine 55 N-(4-((3-(2-amino-4-pyrimidinyl)-2- 432 Apyridinyl)oxy)phenyl)-4,5-difluoro-1H-benzimidazol-2- amine 56N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3- 433 Apyridinyl)-6,7-difluoro-1H-benzimidazol-2-amine 57N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 411 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 58N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 410 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 59N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 425 Apyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine 60N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 61N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 427 Apyridinyl)oxy)phenyl)-1,3-benzothiazol-2-amine 625-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 63N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 478 Apyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H- benzimidazol-2-amine 645-methyl-N-(3-methyl-4-((3-(2-(methylamino)-4- 438 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 65N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 492 Apyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H- benzimidazol-2-amine 661-methyl-N-(3-methyl-4-((3-(2-(methylamino)-4- 438 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 671-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 681-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 492 Apyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H- benzimidazol-2-amine 695,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 446 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 705-(1,1-dimethylethyl)-N-(4-((3-(2-(methylamino)-4- 446 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 716-chloro-5-fluoro-N-(4-((3-(2-(methylamino)-4- 463 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 724-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 735-fluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 428 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 744-methyl-N-(3-methyl-4-((3-(2-(methylamino)-4- 438 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 755-fluoro-N-(3-methyl-4-((3-(2-(methylamino)-4- 442 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 765,6-difluoro-N-(3-methyl-4-((3-(2-(methylamino)-4- 460 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 776-chloro-5-fluoro-N-(3-methyl-4-((3-(2-(methylamino)-4- 476 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 78N-(2-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 424 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 79N-(2,3-dimethyl-4-((3-(2-(methylamino)-4-pyrimidinyl)- 438 A2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 805,6-dimethyl-N-(4-(3-(2-(methylamino)pyrimidin-4- 438 Ayl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine 814,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 446 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 824,5-dimethyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)- 438 A2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 835-fluoro-N-(4-((3-(2-((3-(4-morpholinyl)propyl)amino)-4- 541 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 845,6-dichloro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 478 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 85N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 546 Apyridinyl)oxy)phenyl)-4,6-bis(trifluoromethyl)-1H- benzimidazol-2-amine86 5-chloro-6-methyl-N-(4-((3-(2-(methylamino)-4- 458 Apyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 875-fluoro-N-(4-((3-(2-((4-(4-methyl-1- 588 Apiperazinyl)phenyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 88N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 508 Apyridinyl)oxy)phenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-amine 89 N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2-517 A yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,3-propanediamine 904,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 446 Apyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 91N-(4-((3-(2-((3-(1-piperidinyl)propyl)amino)-4- 571 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine92 N′-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1- 559 F1naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N,2,2-tetramethyl-1,3-propanediamine 935,6-difluoro-N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2- 455 Apyridinyl)oxy) phenyl)-1H-benzimidazol-2-amine 94N-(4-((3-(2-((3-(1H-1,2,3-triazol-1-yl)propyl)amino)-4- 555 F1pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine95 5,6-difluoro-N-(4-((3-(2-((3-(4- 575 F1thiomorpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 96N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2- 531 F1yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,4-butanediamine 972,2′-((3-((4-(2-((4-((5,6-difluoro-1H-benzimidazol-2- 577 F1yl)amino)phenyl)oxy)-3-pyridinyl)-2- pyrimidinyl)amino)propyl)imino)diethanol 98 N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2- 545 F1yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,5-pentanediamine 99N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2- 559 F1yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,6-hexanediamine 100 5,6-difluoro-N-(4-((3-(2-((3-(4- 559 F1morpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 1014,5,6-trifluoro-N-(4-(3-(2-(methylamino)pyrimidin-4- 464 F1yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine 102N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2- 416 F1yloxy)phenyl)-1H-thieno[3,4-d]imidazol-2-amine 103N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2- 419 F1pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 104N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 426 F1pyridinyl)thio)phenyl)-1H-benzimidazol-2-amine 1054,5-difluoro-N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2- 455 F1pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 1064,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 462 F1pyridinyl)thio)phenyl)-1H-benzimidazol-2-amine 1074,5-difluoro-N-(4-((3-(2-((4-(4-methyl-1- 606 F1piperazinyl)phenyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine 1084,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 476 F1pyridinyl)oxy)-3-(methyloxy)phenyl)-1H-benzimidazol-2- amine 109N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 440 F1pyridinyl)oxy)-3-(methyloxy)phenyl)-1H-benzimidazol-2- amine 1104,5-difluoro-N-(3-methyl-4-((3-(2-(methylamino)-4- 460 F1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 1114,5,6,7-tetrafluoro-N-(4-((3-(2-(methylamino)-4- 482 F1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 1124,5-difluoro-N-(2-fluoro-4-((3-(2-(methylamino)-4- 464 F1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2- amine 113N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 486 F1pyridinyl)oxy)phenyl)-1-phenyl-1H-benzimidazol-2- amine 114N-(3-chloro-4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 480 F1pyridinyl)oxy)phenyl)-4,5-difluoro-1H-benzimidazol-2- amine 1154-(2-((4-((1-methyl-4-phenyl-1H-imidazol-2- 436 Eyl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinamine 116N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 460 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 117N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 528 Apyridinyl)oxy)-1-naphthalenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine 118N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2- 461 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 119N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 461 Apyridinyl)oxy)-1-naphthalenyl)-1,3-benzoxazol-2-amine 120N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 477 Apyridinyl)oxy)-1-naphthalenyl)-1,3-benzothiazol-2-amine 1215,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 496 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 1224-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- 474 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine 123N-(4-((3-(2-((2-(4-morpholinyl)ethyl)amino)-4- 559 Apyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine124 6-chloro-5-fluoro-N-(4-((3-(2-(methylamino)-4- 513 Apyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H- benzimidazol-2-amine125 N-(4-((3-(2-(methylsulfanyl)-4-pyrimidinyl)-2- 477 Apyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amineWhile the examples described above provide processes for synthesizingcompounds of Formulas I-III, other methods may be utilized to preparesuch compounds. In the procedures described herein, the steps may beperformed in an alternate order and may be preceded, or followed, byadditional protection/deprotection steps as necessary. The proceduresmay further use appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase, and thelike), extraction, distillation, trituration, reverse phase HPLC and thelike, many of which were utilized in the Examples above. Reactionsconditions such as temperature, duration, pressure, and atmosphere(inert gas, ambient) are known in the art and may be adjusted asappropriate for the reaction.

Methods involving the use of protecting groups may be used.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products. Those of ordinary skill in the art know, orcan easily establish, which protecting groups are suitable with thereactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosauren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Synthetic procedures may also be carried out where functional groups ofstarting compounds, which are not intended to take part in the reaction,may be present in unprotected form without the added step of protectingthat group by, for example, one or more of the protecting groupsmentioned above or taught in the references above.

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Suitableacid and base addition salts are further described in the DefinitionSection herein.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inselect embodiments, such starting materials are used and reactionconditions so selected as to obtain the desired compound(s).

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of the invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, scalemicmixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The compounds of this invention may contain heterocyclic ring systemsattached to another ring system. Such heterocyclic ring systems may beattached through a carbon atom or a heteroatom in the ring system.

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M.Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductionsby the Alumino- and Borohydrides in Organic Synthesis, 2^(nd) edition,Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion. By way of example, a compound ofthe invention may be modified to incorporate a hydrophobic group or“greasy” moiety in an attempt to enhance the passage of the compoundthrough a hydrophobic membrane, such as a cell wall.

These detailed descriptions fall within the scope, and serve toexemplify, the above-described General Synthetic Procedures which formpart of the invention. These detailed descriptions are presented forillustrative purposes only and are not intended as a restriction on thescope of the invention.

Biological Evaluation

Although the pharmacological properties of the compounds of theinvention (Formulas I-III) vary with structural change, in general,activity possessed by compounds of Formulas I-III may be demonstratedboth in vitro as well as in vivo. Particularly, the pharmacologicalproperties of the compounds of this invention may be confirmed by anumber of pharmacological in vitro and/or in vivo assays. The followingexemplified pharmacological assays have been carried out with thecompounds according to the invention. Briefly, representative compoundsof the invention were found to inhibit the activity of the Tie-2receptor kinase and Aurora kinase, selectively or non-selectively, atdoses less than 25 μM. This activity demonstrates the utility of thecompounds of the invention as protein kinase inhibitors and in theprophylaxis and treatment of oncological conditions, cell proliferativedisorders, cancer, and the like, as described herein.

The following assays can be employed to determine the degree of activityof a compound as a protein kinase inhibitor.

Tie-2-Homogenous Time Resolved Flourescent (HTRF) Kinase Assay

IC₅₀'s for the inhibition of the Tie-2 kinase enzyme for individualcompounds were measured using an HTRF assay, utilizing the followingprocedure:

In a 96-well plate (available from Costar Co.) was placed 1 uL of eachtest and standard compound per well in 100% DMSO having a 25 uM finalcompound concentration (3-fold, 10 point dilution). To each well wasadded 20 uL of a reaction mix formed from Tie-2 (4.0 uL; of a 10 mMstock solution available from Gibco), 0.05% BSA (0.1 uL; from a 10%stock solution available from Sigma-Aldrich Co.), 0.002 mM of BLC HER-2KKK (Biotinylated Long chain peptide; 0.04 uL; from a 0.002 mM stocksolution), 0.01 mM concentration of ATP (0.02 uL; commercially availablefrom Sigma-Aldrich Co.) and the remaining solution was water (15.84 uL)to make to a total volume of 20 uL/well.

The reaction was initiated in each well by adding 20 uL per well of anenzyme preparation consisting of a 50 mM concentration of Hepes (1.0 uL;from a 1000 mM stock solution commercially available from Gibco Co.),0.05% concentration of BSA (0.1 uL), 4 mM of DTT (0.08 uL; from a 1000mM stock solution available from Sigma-Aldrich Co.), a 2.4×10⁻⁷concentration of Tie-2 (0.02 uL, from a 4 mM concentration stock), withthe remaining volume being water (18.8 uL) to dilute the enzymepreparation to a total volume of 20 uL. The plate was incubated forabout 90 minutes at RT. After incubation, a 160 uL of a filtereddetection mixture, prepared from 0.001 mg/ml of SA-APC (0.0765 uL;available as a 2.09 mg/ml stock solution from Gibco), 0.03125 nMconcentration of Eu-Ab (0.1597 uL; available in a 31.3 nM stock solutionfrom Gibco), with the remaining volume being Detection buffer (159.73uL), was added to each well to stop the reaction therein. The plate wasthen allowed to equilibrate for about 3 hr and read on a Ruby Starfluorescent reader (available from BMG Technologies, Inc.) using a 4parameter fit using activity base to calculate the corresponding IC₅₀'sfor the test and standard compounds in each well. Examples 4-6, 8-46,51-61, 63-65, 68-103 and 105-115 were found to have IC₅₀'s for theinhibition of Tie-2 as measured by the HTRF assay of less than or equalto 5 uM.

The compounds of the invention also were found to have inhibitoryactivity with respect to Aurora kinase enzymes. The exemplary assaysdescribed as follows were used to make such determination.

Aurora Kinase HTRF Assays

AuroraA-TPX2-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The AuroraA HTRF assay begins with AuroraA in the presence of ATPphosphorylating the biotinylated peptide PLK. The reaction incubates forabout 120 min. Detection reagents are added to quench the reaction.These agents stop the reaction by diluting out the enzyme and chelatingthe metals due to the presence of EDTA. After addition, the assay isincubated overnight to allow the detection reagents to equilibrate.

The AuroraA HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated PLK, and 20 μL of AuroraA-TPX2 KD GST for a finalvolume of 41 μL. The final concentration of PLK is about 1 μM. The finalconcentration of ATP is about 1 μM (Km(app)=1 μM+/−0.1) and the finalconcentration of AuroraA is about 5 nM. Buffer conditions are asfollows: 60 mM HEPES pH 7.5, 25 mM NaCl, 10 mM MgCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.0005 mg/mL, and europilated anti-phosphoPLK Ab(Eu-anti-PLK) at a fmal conc of 0.02 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-PLK is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-PLK because ofphosphorylation of the peptide) to free Eu-anti-PLK at 615 nm will givesubstrate phosphorylation.

The following exemplary compounds 5-7, 10-12, 15-26, 28-38, 46, 48,51-54, 57-106 and 115, exhibited IC₅₀ activity of less than or equal to5 μM in the Aurora kinase A HTRF assay.

AuroraB-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The AuroraB HTRF assay begins with AuroraB in the presence of ATPphosphorylating the biotinylated peptide Histone H3. The reactionincubates for about 90 min. the reaction is quentched by addition ofdetection reagents, which stop the reaction by diluting out the enzymeand chelating the metals due to the presence of EDTA. After addition,the assay is incubated for about 60 min to allow detection reagents toequilibrate.

The AuroraB HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated Histone H3, and 20 μL of AuroraB FL His for a finalvolume of 41 μL. The final concentration of Histone H3 is 0.1 μM. Thefinal concentration of ATP is 23 μM (Km(app)=23 μM+/−2.6) and the finalconcentration of AuroraB is 400 pM. Buffer conditions are as follows: 50mM HEPES pH 7.5, 5 mM NaCl, 0.5 mM MgCl, 0.5 mM MnCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.001 mg/mL, and europilated anti-phosphoHistoneH3 Ab(Eu-anti-HisH3) at a final conc of 0.064 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-HisH3 is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-HisH3 because ofphosphorylation of the peptide) to free Eu-anti-HisH3 at 615 nm willgive substrate phosphorylation.

The following exemplary compounds 4-6, 8-46 and 51-115, exhibited IC₅₀activity of less than or equal to 5 μM in the Aurora kinase B HTRFassay.

Indications

The compounds of the invention have kinase modulatory activity for bothTie-2 and Aurora kinase. In one embodiment of the invention, there isprovided a method of modulating tie-2 or Aurora kinase in a subject, themethod comprising administering to the subject an effective dosageamount of a compound of a compound of Formulas I-III.

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of angiogenesis and cell-cycling andcell proliferation-related diseases. The compounds may be useful for thetreatment of neoplasia including cancer and metastasis, including, butnot limited to: carcinoma such as cancer of the bladder, breast, colon,kidney, liver, lung (including small cell lung cancer), esophagus,gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, andskin (including squamous cell carcinoma); hematopoietic tumors oflymphoid lineage (including leukemia, acute lymphocitic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett'slymphoma); hematopoietic tumors of myeloid lineage (including acute andchronic myelogenous leukemias, myelodysplastic syndrome andpromyelocytic leukemia); tumors of mesenchymal origin (includingfibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissueand bone); tumors of the central and peripheral nervous system(including astrocytoma, neuroblastoma, glioma and schwannomas); andother tumors (including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma). The compounds are useful forthe treatment of neoplasia selected from lung cancer, colon cancer andbreast cancer.

The compounds of the invention are also useful in the treatment ofcancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formulas I-III inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The pharmaceutically active compounds of this invention canbe processed in accordance with conventional methods of pharmacy toproduce medicinal agents for administration to patients, includinghumans and other mammals.

The compounds of the present invention may be administered to a subjectby any suitable route, preferably in the form of a pharmaceuticalcomposition, adapted to such a route, and in a dose effective for thetreatment intended. The compounds and compositions of the presentinvention may, for example, be administered orally, mucosally,topically, rectally, pulmonarily such as by inhalation spray, orparentally including intravascularly, intravenously, intraperitoneally,subcutaneously, intramuscularly intrasternally and infusion techniques,in dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid, which canbe made using known, conventional methods. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules. For example, these may contain an amountof active ingredient from about 1 to 2000 mg, and typically from about 1to 500 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods and practices.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, and more advantageously about 0.01 and about 30 mg/kgbody weight may be appropriate. The daily dose can be administered inone to four doses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If administered ona per dose basis, the compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to formthe final formulation. For example, the active compound(s) andexcipient(s) may be tableted or encapsulated by known and acceptedmethods for convenient administration. Examples of suitable formulationsinclude, without limitation, pills, tablets, soft and hard-shell gelcapsules, troches, orally-dissolvable forms and delayed orcontrolled-release formulations thereof. Particularly, capsule or tabletformulations may contain one or more controlled-release agents, such ashydroxypropylmethyl cellulose, as a dispersion with the activecompound(s).

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, pastes, suspensions andthe like) and drops suitable for administration to the eye, ear, ornose. A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I-III may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanticancer or cytotoxic agent.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art, are intendedto be within the scope and nature of the invention, which are defined inthe appended claims.

All mentioned references, patents, applications and publications, arehereby incorporated by reference in their entirety, as if here written.

1. A compound of Formula I:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein A is

wherein each of A¹ and A³ independently, is N or CR⁸ and A² is NR⁹, O orS; B is a fully unsaturated 5-6 membered first monocyclic ring, saidfirst ring (1) formed of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, (2) optionally fused to apartially or fully saturated or fully unsaturated 5-6 membered secondmonocyclic ring formed of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and (3) wherein 0, 1, 2 or 3 atomsof each of said first and second ring is optionally substitutedindependently with 1-4 substituents of R⁵; C¹ is N or CR¹⁰; C² is N orCH; D is

wherein D¹ is N or CR¹¹; D²is N or CR¹²; R¹ is H, OR¹⁴, SR¹⁴, OR¹⁵,SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵, wherein nis 0, 1, 2, 3 or 4; R^(1a) is H, CN or C₁₋₁₀alkyl; alternatively R¹taken together with either of R¹¹ and R^(1a) and the carbon or nitrogenatoms to which they are attached form a partially or fully unsaturated5- or 6-membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with 1-3 substituents of R¹⁵, SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵;and R² is SR¹⁴, OR¹⁴, SR¹⁴, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵; L¹ is NR³, O, S, C(O), S(O), SO₂ or CR³R³; L² isNR³, O, S, C(O), S(O), SO₂ or CR³R³; each of R³ and R⁴, independently,is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵,NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵ or R¹⁵;alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵; each R⁵, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;alternatively, R⁶ and R⁷ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N, or S, and the ring optionally substituted independently with 1-4substituents of R¹³, R¹⁴ or R¹⁵; R⁹ is R¹⁵; each of R¹⁰, R¹¹ and R¹²,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵, OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂N¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ isa partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-3 substituents of R¹⁵; and R¹⁵ is H, halo,haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; provided that (1) no more than oneof D¹ and D² is N, and (2) each of L¹ and L² is, independently, bound tothe first ring of B.
 2. The compound of claim 1, wherein D¹ is N, D² isCR¹².
 3. The compound of claim 1, wherein D² is N and D¹ is CR¹¹.
 4. Thecompound of claim 1, wherein C¹ is CR¹⁰; C² is N; and R² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀-alkoxyl.
 5. The compound of claim 1,wherein L¹ is NR¹⁵, O, CHR¹⁵, S, C(O), S(O) or SO₂; and R² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀-alkoxyl.
 6. The compound of claim 1,wherein each of L¹ and L², independently, is CHR¹⁵, NR¹⁵, O, S, or C(O);R² is H, halo, NO₂, CN, C₁₋₁₀, loalkyl or C₁₋₁₀alkoxyl; each of R³, R⁴and R⁹, independently, is H; and C¹ is CR¹⁰.
 7. The compound of claim 1,wherein the first monocyclic ring of B is phenyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, or isothiazolyl; and where the firstmonocyclic ring of B is a fully unsaturated 6-membered ring, then L¹ andL², together, are para to one another on said first monocyclic ring ofB.
 8. The compound of claim 7, wherein R⁶ and R⁷ taken together with thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 nitrogen atoms, and the ring optionally substituted independentlywith 1-4 substituents of R¹³, R¹⁴ or R¹⁵.
 9. The compound of claim 8,wherein A is

wherein A¹ is N and A² is NH, O or S.
 10. The compound of claim 9,wherein R⁶ and R⁷ taken together with the carbon atoms to which they areattached form a phenyl ring optionally substituted independently with1-3 substituents of R¹⁵.
 11. The compound of claim 1, wherein A is


12. The compound of claim 1, wherein A is


13. A compound of Formula II:

and pharmaceutically acceptable salts thereof, wherein A¹ is N or CR⁸;A² is NR⁹, O or S; A′ is phenyl, pyridine, pyrimidine or pyridazine,each of which is optionally substituted independently with 1-3substituents of R¹³, R¹⁴ or R¹⁵; each of B¹, B², B³ and B⁴,independently, is N or CR¹⁵, provided that no more than two of B¹, B²,B³ and B⁴ is N; alternatively, each of B¹ and B², independently, is CR⁵,wherein both R⁵ groups taken together with the carbon atoms to whichthey are attached form a 5- or 6-membered ring of carbon atoms, saidring optionally including 1-3 heteroatoms selected from N, O or S, andoptionally substituted with 1-4 substituents of R¹³, R¹⁴ or R¹⁵; C¹ is Nor CR¹⁰; D¹ is N or CR¹¹; D² is N or CR¹²; L¹ is NR³, O, S or CR³R³; L²is NR³, O, S or CR³R³; R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,(CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵, wherein n is 0, 1, 2, 3 or 4;alternatively R¹ and R¹¹ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N and S, and the ring optionally substituted independently with 1-4substituents of R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵; R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR^(15 S(O)) ₂R¹⁵ or R¹⁵; each of R³ and R⁴,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵ or R¹⁵; alternatively, either of R³ or R⁴, independently, takentogether with R¹⁰ and the carbon atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R¹³,R¹⁴ or R¹⁵; each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵,C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴,S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; R⁸ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵or R¹⁵; R⁹ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂,NH₂, acetyl, C₁₋₁₀-alkyl, C₁₋₁₀-alkoxyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl ora saturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₁₋₁₀-alkoxyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, and ringof said ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; each of R¹⁰, R¹¹ and R¹²,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵ or R¹⁵; R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵),NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ is a partially or fully saturated or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, the ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected fromO, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionallysubstituted independently with 1-3 substituents of R¹⁵; and R¹⁵ is H,halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-alkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; provided that no more than one of D¹and D² is N.
 14. The compound of claim 13, wherein A¹ is N; A² is NR⁹, Oor S; each of B¹, B², B³ and B⁴, independently, is CR⁵; C¹ is CR¹⁰; D¹is N or CR¹¹; D² is N or CR¹²; L¹ is NH, O or S; L² is NH, O or S; R¹ isH, halo, haloalkyl, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, NHR¹⁴, NHR¹⁵, OR¹⁵, SR¹⁵ or CH₂R¹⁵; R²is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl; each of R³ and R⁴,independently, is SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;each R⁵ is, independently, is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁵), S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or R¹⁵; and R⁸ isSR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵ or R¹⁵; R⁹ is H, CN, acetyl or C₁₋₁₀-alkyl;and each of R¹⁰, R¹¹ and R¹², independently, is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; provided that no more than one of D¹ and D² isN.
 15. The compound of claim 13 wherein, R¹ is NR¹⁴R¹⁵, NR¹⁵R¹⁵,(CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternatively R¹ and R¹¹ takentogether with the carbon atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S, and thering optionally substituted independently with 1-4 substituents of R¹⁵;R² is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl; each of R³ and R⁴, independently, is H, halo, haloalkyl, CN,NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine,dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine,dipropylamine, diisopropylamine, benzyl or phenyl; each R¹⁵ is,independently, is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylaamine,diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine; R⁸ is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine; R⁹ is H or C₁₋₁₀-alkyl; and each of R¹⁰, R¹¹ and R¹²,independently, is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine.
 16. A compound of Formula III:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein A¹ is N or CR⁸; A² is NR⁹, O orS; each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided thatno more than two of B¹, B², B³ and B⁴ is N; C¹ is N or CR¹⁰; L¹ is O, S,C(O), S(O), SO₂ or CR³R³; L² is NR³, O, S or CR³R³; R¹ is OR¹⁴, SR¹⁴,OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵; R²is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵,OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵; each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; alternatively,either of R³ or R⁴, independently, taken together with R¹⁰ and thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵; eachR⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, COR¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, N¹⁵COR¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;alternatively, R⁶ and R⁷ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N, or S, and the ring optionally substituted independently with 1-4substituents of R¹³, R¹⁴ or R¹⁵; R⁹ is R¹⁵; each of R¹⁰,R¹¹ and R¹²,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵ or R¹⁵; R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵),NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ is a partially or fully saturated or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, the ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected fromO, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionallysubstituted independently with 1-3 substituents of R¹⁵; R¹⁵ is H, halo,haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamnine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and n is 0, 1, 2, 3 or
 4. 17. Thecompound of any of claim 1 and pharmaceutically acceptable saltsthereof, selected from:N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine;N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1,3-benzoxazol-2-amine;N-(4-((3-(2-(methylaino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1,3-benzothiazol-2-amine;5,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-((2-(4-morpholinyl)ethyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylsulfanyl)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylsulfonyl)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1-H-benzimidazol-2-amine;5,7-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(1-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1-naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N-4-,N-4-dimethyl-1,4-butanediamine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-5,7-bis(trifluoromethyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-3H-imidazo[4,5-b]pyridin-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-3H-imidazo[4,5-c]pyridin-2-amine;N-(4-((3-(2-((3-(1-pyrrolidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(3,5-dichloro-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-1H-benzimidazol-2-yl-8-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-5-quinolinamine;4,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;6,7-difluoro-N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-1H-benzimidazol-2-amine;N-(4-((2-(2-(methylamino)-4-pyrimidinyl)phenyl)oxy)phenyl)-1H-benzimidazol-2-amine;6,7-difluoro-N-(4-((2-(2-(methylamino)-4-pyrimidinyl)phenyl)oxy)phenyl)-1H-benzimidazol-2-amine;2-((4-((6,7-difluoro-1H-benzimidazol-2-yl)amino)phenyl)oxy)-N-methyl-3,4′-bipyridin-2′-amine;N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-methyl--naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-((2-(1-methyl-2-pyrrolidinyl)ethyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1-H-benzimidazol-2-amine;5,7-dimethyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine;6-methyl-N-(3-methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine;N-(4-((3-(2-(((1-ethyl-4-piperidinyl)methyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-((1-methyl-4-piperidinyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine4,5-difluoro-N-(4-((3-(1H-pyrazol-4-yl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4,5-difluoro-1H-benzimidazol-2-amine;N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-6,7-difluoro-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine;N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1,3-benzoxazol-2-amine;N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine;5-methyl-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine;1-methyl-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;1-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;1-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-amine;5,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-(1,1-dimethylethyl)-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;6-chloro-5-fluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-fluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-fluoro-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5,6-difluoro-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;6-chloro-5-fluoro-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(2-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-H-benzimidazol-2-amine;N-(2,3-dimethyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5,6-dimethyl-N-(4-(3-(2-(methylamino)pyramidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;4,6-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-fluoro-N-(4-((3-(2-((3-(4-morpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4,6-bis(trifluoromethyl)-1H-benzimidazol-2-amine;5-chloro-6-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5-fluoro-N-(4-((3-(2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-amine;N′-(4-(2-((4-((5,6-difluoro-1-H-benzimidazol-2-yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,3-propanediamine;4,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-H-benzimidazol-2-amine;N-(4-((3-(2-((3-(1-piperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N′-(4-(2-((4-(1H-benzimidazol-2-ylamino)-1-naphthalenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N,2,2-tetramethyl-1,3-propanediamine;5,6-difluoro-N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;5,6-difluoro-N-(4-((3-(2-((3-(4-thiomorpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2-yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,4-butanediamine;2,2′-((3-((4-(2-((4-((5,6-difluoro-1H-benzimidazol-2-yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)amino)propyl)imino)diethanol;N′-(4-(2-((4-((5,6-difluoro-1H-benzimidazol-2-yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-N,N-dimethyl-1,6-hexanediamine;5,6-difluoro-N-(4-((3-(2-((3-(4-morpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4,5,6-trifluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1-H-thieno[3,4-d]imidazol-2-amine;N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)thio)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(4-((3-(2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-(methyloxy)phenyl)-1-H-benzimidazol-2-amineN-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-(methyloxy)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-H-benzimidazol-2-amine;4,5,6,7-tetrafluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;4,5-difluoro-N-(2-fluoro-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-phenyl-1H-benzimidazol-2-amine;N-(3-chloro-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4,5-difluoro-1H-benzimidazol-2-amine;4-(2-((4-((4-methyl-1-phenyl-1H-pyrazol-3-yl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinamine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1,3-benzoxazol-2-amine;N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1,3-benzothiazol-2-amine;4-methyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;N-(4-((3-(2-((2-(4-morpholinyl)ethyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amine;6-chloro-5-fluoro-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1-H-benzimidazol-2-amine;N-(4-((3-(2-(methylsulfanyl)-4-pyrimidinyl)-2-pyridinyl)oxy)-1-naphthalenyl)-1H-benzimidazol-2-amineand combinations thereof.
 18. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective dosage amount ofthe compound of claim
 1. 19. A method of treating cancer in a subject,the method comprising administering to the subject an effective dosageamount of the compound of claim
 1. 20. A method of reducing the size ofa solid tumor in a subject, the method comprising administering to thesubject an effective dosage amount of the compound of claim
 1. 21. Amethod of treating a disorder related to the activity of Aurora Kinasein a subject, the method comprising administering to the subject aneffective dosage amount of the compound of claim
 1. 22. The method ofclaim 21 wherein the disorder is a cancer selected from bladder, breast,colon, kidney, liver, lung, small cell lung cancer, esophagus,gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate andskin; a hematopoietic tumor of lymphoid lineage selected from leukemia,acute lymphocitic leukemia, acute lymphoblastic leukemia, B-celllymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,hairy cell lymphoma and Burkett's lymphoma; a hematopoietic tumor ofmyeloid lineage selected from acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; a tumor ofmesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; atumor of the central and peripheral nervous system selected fromastrocytoma, neuroblastoma, glioma and schwannomas; a melanoma,seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,keratoctanthoma, thyroid follicular cancer or Kaposi's sarcoma; or acombination thereof.
 23. A method of making a compound of claim 1, themethod comprising the step of reacting compound of Formula A

with a compound of Formula B

wherein A, B, C¹, C², D, L¹, L² and R³⁻⁴ are defined in claim 1 and X isa halogen, to make a compound of Formula I.